document_title: The Prince of Egypt

question_text: who played moses mother in prince of egypt

text: The Prince of Egypt

text: Plot[edit]

text: In Ancient Egypt, Yocheved and her two young children, Miriam and Aaron, watch as the newborn Hebrew boys are taken and ruthlessly killed as ordered by Pharaoh Seti, who fears that an alarming increase of Hebrew slaves could lead to rebellion. Fearing for her own newborn son's safety, Yocheved places him in a basket afloat on the Nile River, not before bidding him farewell with a final but powerful lullaby. Miriam follows the basket as it sails to the Pharaoh's palace and witnesses her baby brother safely adopted by Seti's wife Queen Tuya, who names him Moses.

text: Years later, Moses and his now brother Rameses ,son of Pharaoh Seti, are scolded by their father for accidentally destroying a temple during one of their youthful misadventures. At Moses' suggestion, Seti, seeking to give Rameses the opportunity to prove that he is a responsible young man, names him Prince Regent and gives him authority over Egypt's temples. As a tribute, the high priests Hotep and Huy offer him a beautiful young Midianite woman, Tzipporah, whom Rameses gives to Moses, appointing him Royal Chief Architect.

text: Later that night, Moses follows Tzipporah as she escapes from the palace, and runs into the now-adult Miriam and Aaron, but he does not recognize them. Miriam then sings her mother's lullaby, which Moses remembers; however, he returns to the palace, eager to go back to familiar surroundings. The truth about his past is later confirmed by a nightmare, and finally by Seti himself, who disturbs Moses by claiming the Hebrews were "only slaves". The next day, Moses accidentally pushes an Egyptian guard to his death while trying to stop him from whipping an elderly Hebrew slave. Horrified and ashamed, Moses flees into the desert in exile, despite Rameses' pleas that he stay.

text: While in the desert Moses defends three young girls from brigands, only to find out their older sister is Tzipporah herself. Moses is welcomed by Tzipporah's father and the high priest of Midian, Jethro. After assimilating into this new culture, Moses becomes a shepherd and marries Tzipporah. One day, while chasing a stray lamb, Moses discovers a burning bush through which God tells him to go back to Egypt and guide the Hebrew slaves to freedom. God bestows Moses' shepherding staff with his power and promises that he will tell Moses what to say. Moses and Tzipporah return to Egypt, where Moses is happily greeted by Rameses, who is now Pharaoh.

text: When Moses requests the Hebrews release and changes his staff into an Egyptian cobra to demonstrate his alliance with God, Hotep and Huy boastfully recreate this transformation, only to have their snakes eaten by Moses' snake. Rather than be persuaded, Rameses hardens and doubles the Hebrews workload. Moses inflicts nine of the Plagues of Egypt, but still Rameses refuses to relent and, against Moses' warning (foreshadowing the final plague), vows never to release the Hebrews slaves. Disheartened, Moses prepares the Hebrews for the tenth and final plague, instructing them to sacrifice a lamb and mark the doorposts with the lamb's blood. That night, the final plague kills all the firstborn children of Egypt, including Rameses' son, while sparing those of the Hebrews. A grief-stricken Rameses finally gives Moses permission to free the Hebrews. After leaving the palace, Moses collapses weeping with grief, heartbroken at the pain he has caused his brother and Egypt.

text: The following morning, the Hebrews leave Egypt, led by Moses, Miriam, Aaron, and Tzipporah. At the Red Sea, they discover that a vengeful Rameses is pursuing them with his army, intent on killing them. However, a writhing pillar of fire blocks the army's way, while Moses uses his staff to part the sea. The Hebrews cross the open sea bottom; after that, the fire vanishes and the army gives chase, but the water closes over and drowns the Egyptian soldiers, sparing Rameses alone. Moses sadly bids farewell to his brother and leads the Hebrews to Mount Sinai, where he receives the Ten Commandments.

text: Cast[edit]

text:
Val Kilmer as Moses, a Jew who was adopted by Pharaoh Seti I and Queen Tuya.
Val Kilmer also provides the uncredited voice of God
Amick Byram provides Moses' singing voice.
Ralph Fiennes as Ramesses II, Moses' brother and eventual successor to his father Seti.
Michelle Pfeiffer as Tzipporah, Jethro's oldest daughter and Moses' wife.
Sandra Bullock as Miriam, Aaron's sister, Moses' biological sister.
Sally Dworsky provides Miriam's singing voice.
Eden Riegel provides the voice of a younger Miriam.
Jeff Goldblum as Aaron, Miriam's brother, Moses' biological brother.
Danny Glover as Jethro, Tzipporah's father and Midian's high priest.
Brian Stokes Mitchell provides Jethro's singing voice.
Patrick Stewart as Seti, Rameses' and Moses' father,  the first Pharaoh in the film.
Helen Mirren as Tuya, Seti's wife, Rameses' and Moses' mother.
Linda Dee Shayne provides Tuya's singing voice.
Steve Martin as Hotep, one of the high priests who serves as advisor to Seti, and later Rameses.
Martin Short as Huy, Hotep's fellow high priest.
Ofra Haza as Yocheved, the mother of Miriam and Aaron and birth mother of Moses. She also sang her character's number, "Deliver Us", in seventeen other languages for the film's dubbing[8])
Bobby Motown as Ramses' son

text: Director Brenda Chapman briefly voices Miriam when she sings the lullaby to Moses. The vocals had been recorded for a scratch audio track, which was intended to be replaced later by Sally Dworsky. The track turned out so well that it remained in the film.

text: Production[edit]

text: Development[edit]

text: Former Disney chairman Jeffrey Katzenberg had always wanted to do an animated adaptation of The Ten Commandments. While working for The Walt Disney Company, Katzenberg suggested this idea to Michael Eisner, but he refused. The idea for the film was brought back at the formation of DreamWorks SKG in 1994, when Katzenberg's partners, Amblin Entertainment founder Steven Spielberg, and music producer David Geffen, were meeting in Spielberg's living room.[9] Katzenberg recalls that Spielberg looked at him during the meeting and said, "You ought to do The Ten Commandments."[9]

text: The Prince of Egypt was "written" throughout the story process. Beginning with a starting outline, Story Supervisors Kelly Asbury and Lorna Cook led a team of fourteen storyboard artists and writers as they sketched out the entire film — sequence by sequence. Once the storyboards were approved, they were put into the Avid Media Composer digital editing system by editor Nick Fletcher to create a "story reel" or animatic. The story reel allowed the filmmakers to view and edit the entire film in continuity before production began, and also helped the layout and animation departments understand what is happening in each sequence of the film.[10]  After casting of the voice talent concluded, dialogue recording sessions began. For the film, the actors record individually in a studio under guidance by one of the three directors. The voice tracks were to become the primary aspect as to which the animators built their performances.[10] Because DreamWorks was concerned about theological accuracy, Jeffrey Katzenberg decided to call in Biblical scholars, Christian, Jewish and Muslim theologians, and Arab American leaders to help his film be more accurate and faithful to the original story. After previewing the developing film, all these leaders noted that the studio executives listened and responded to their ideas, and praised the studio for reaching out for comment from outside sources.[9]

text: Design and animation[edit]

text: Art directors Kathy Altieri and Richard Chavez and Production Designer Darek Gogol led a team of nine visual development artists in setting a visual style for the film that was representative of the time, the scale and the architectural style of Ancient Egypt.[10] Part of the process also included the research and collection of artwork from various artists, as well as taking part in trips such as a two-week journey across Egypt by the filmmakers before the film's production began.[10]

text: Character Designers Carter Goodrich, Carlos Grangel and Nicolas Marlet worked on setting the design and overall look of the characters. Drawing on various inspirations for the widely known characters, the team of character designers worked on designs that had a more realistic feel than the usual animated characters up to that time.[10] Both character design and art direction worked to set a definite distinction between the symmetrical, more angular look of the Egyptians versus the more organic, natural look of the Hebrews and their related environments.[10] The Backgrounds department, headed by supervisors Paul Lasaine and Ron Lukas, oversaw a team of artists who were responsible for painting the sets/backdrops from the layouts. Within the film, approximately 934 hand-painted backgrounds were created.[10]

text: The animation team for The Prince of Egypt, including 350 artists from 34 different nations, was primarily recruited both from Walt Disney Feature Animation,[11] which had fallen under Katzenberg's auspices while at The Walt Disney Company, and from Amblimation, a defunct division of Steven Spielberg's Amblin Entertainment.[12] As at Disney's, character animators were grouped into teams by character: for example, Kristof Serrand, as the supervising animator of Older Moses, set the acting style of the character and assigned scenes to his team.[13] Consideration was given to depicting the ethnicities of the ancient Egyptians, Hebrews, and Nubians properly.[14]

text: There are 1,192 scenes in the film, and 1,180 contain work done by the special effects department, which animates everything in an animated scene which is not a character: blowing wind, dust, rainwater, shadows, etc. A blend of traditional animation and computer-generated imagery was used in the depictions of the ten plagues of Egypt and the parting of the Red Sea.[9][15] The animated characters were digitally inked and paint software using Cambridge Systems' Animo software system (now merged with Toon Boom),[16] and the compositing of the 2D and 3D elements was done using the "Exposure Tool", a digital solution developed for DreamWorks by Silicon Graphics.[15][17]

text: Creating the voice of God[edit]

text: The task of creating God's voice was given to Lon Bender and the team working with the film's music composer, Hans Zimmer.[18] "The challenge with that voice was to try to evolve it into something that had not been heard before," says Bender. "We did a lot of research into the voices that had been used for past Hollywood movies as well as for radio shows, and we were trying to create something that had never been previously heard not only from a casting standpoint but from a voice manipulation standpoint as well. The solution was to use the voice of actor Val Kilmer to suggest the kind of voice we hear inside our own heads in our everyday lives, as opposed to the larger than life tones with which God has been endowed in prior cinematic incarnations."[18] Although, in The Ten Commandments (1956 film), Charlton Heston, who played Moses, also provided the voice of God.

text: Music[edit]

text: Composer and lyricist Stephen Schwartz began working on writing songs for the film from the beginning of its production. As the story evolved, he continued to write songs that would serve both to entertain and help move the story along. Composer Hans Zimmer arranged and produced the songs and then eventually wrote the film's score. The film's score was recorded entirely in London, England.[10]

text: Three soundtrack albums were released simultaneously for The Prince of Egypt, each of them aimed towards a different target audience. While the other two accompanying records, the country-themed "Nashville" soundtrack and the gospel-based "Inspirational" soundtrack, functioned as film tributes, the official The Prince of Egypt soundtrack contained the actual songs from the film.[19] This album combines elements from the score composed by Hans Zimmer and film songs by Stephen Schwartz.[19] The songs were either voiced over by professional singers, such as Salisbury Cathedral Choir, or sung by the film's voice actors, such as Michelle Pfeiffer and Ofra Haza. Various tracks by contemporary artists such as K-Ci & JoJo and Boyz II Men were added, including the Mariah Carey and Whitney Houston duet "When You Believe", a Babyface rewrite of the original Schwartz composition, sung by Michelle Pfeiffer and Sally Dworsky in the film.

text: Musical numbers[edit]

text:
"Deliver Us" – Ofra Haza, Eden Riegel, and Chorus
"River Lullaby" - Brenda Chapman
"All I Ever Wanted" – Amick Byram
"All I Ever Wanted (Queen's Reprise)" – Linda Dee Shayne
"Through Heaven's Eyes" – Brian Stokes Mitchell
"Playing with the Big Boys" – Steve Martin and Martin Short
"The Plagues" – Byram, Ralph Fiennes, and Chorus
"When You Believe" – Sally Dworsky, Michelle Pfeiffer, and Chorus

tag: ol

text: Release[edit]

text: The Prince of Egypt had its premiere at the UCLA's Royce Hall on December 16, 1998,[2] with its wide release occurring two days later.[5] Despite being the inaugural production by DreamWorks Animation, it wound up the second to get a theatrical release, as Antz was rushed to reach theatres in September.[20] The international release occurred simultaneously with that of the United States, as according to DreamWorks' distribution chief Jim Tharp, opening one week prior to the "global holiday" of Christmas, audiences all over the world would be available at the same time.[21]

text: The accompanying marketing campaign was aimed to appeal to adults, usually averse to animated films. Merchandising was limited to a line of collectable figures and books.[22] Wal-Mart served as a promotional partner and offered in stores a package featuring two tickets to The Prince of Egypt, a storybook and the film's soundtrack.[23]

text: Home media[edit]

text: The Prince of Egypt was released on DVD and VHS on September 14, 1999.[24] The ownership of the film was assumed by DreamWorks Animation when that company split from DreamWorks Pictures in 2004; as of July 2018, the rights to the film are now owned by Universal Pictures via its acquisition of DWA. As with the rest of the DreamWorks Animation catalog, it is available for streaming on Netflix in HD.[25] However, both the DVD release and the streaming versions used a 35mm print of the film, rather than using the original files to encode the movie directly to digital.

text: Reception[edit]

text: Box office performance[edit]

text: On its opening weekend, the film grossed $14.5 million for a $4,658 average from 3,118 theaters, earning second place at the box office, behind You've Got Mail. Due to the holiday season, the film gained 4% in its second weekend, earning $15.1 million and finishing in fourth place. It had a $4,698 average from 3,218 theaters. It would hold well in its third weekend, with only a 25% drop to $11,244,612 for a $3,511 average from 3,202 theaters and once again finishing in fourth place. The film closed on May 27, 1999 after earning $101.4 million in the United States and Canada with an additional $117.2 million overseas for a worldwide total of $218.6 million. The Prince of Egypt was the second non-Disney animated feature to gross over $100 million in the U.S. after Paramount/Nickelodeon's The Rugrats Movie. It remained the top-grossing non-Disney animated film until being surpassed by the 2000 stop-motion film Chicken Run, also distributed by DreamWorks, and remained the highest-grossing traditionally animated non-Disney film until 2007, when it was out-grossed by 20th Century Fox's The Simpsons Movie.[26]

text:
The Prince of Egypt box office revenue

Source
Gross (USD)
% Total
All Time Rank (Unadjusted)

United States and Canada

$101.4 million[5]

46.4%

398[5]

Foreign

$117.2 million[5]

53.6%

–

Worldwide

$218.6 million[5]

100.0%

319[5]

text: Critical response[edit]

text: The film has a rating of 79% on Rotten Tomatoes based on 84 reviews, with a weighted average score of 7/10. The site's consensus reads, "The Prince of Egypt's stunning visuals and first-rate voice cast more than compensate for the fact that it's better crafted than it is emotionally involving."[27] Metacritic, which assigns a normalized 0–100 rating to reviews from mainstream critics, calculated an average score of 64 from the 26 reviews it collected.[28]

text: Roger Ebert of the Chicago Sun-Times praised the film in his review saying, "The Prince of Egypt is one of the best-looking animated films ever made. It employs computer-generated animation as an aid to traditional techniques, rather than as a substitute for them, and we sense the touch of human artists in the vision behind the Egyptian monuments, the lonely desert vistas, the thrill of the chariot race, the personalities of the characters. This is a film that shows animation growing up and embracing more complex themes, instead of chaining itself in the category of children's entertainment."[29] Richard Corliss of Time magazine gave a negative review of the film saying, "The film lacks creative exuberance, any side pockets of joy."[30] Stephen Hunter from The Washington Post praised the film saying, "The movie's proudest accomplishment is that it revises our version of Moses toward something more immediate and believable, more humanly knowable."[31]

text: Lisa Alspector from the Chicago Reader praised the film and wrote, "The blend of animation techniques somehow demonstrates mastery modestly, while the special effects are nothing short of magnificent."[32] Houston Chronicle's Jeff Millar reviewed by saying, "The handsomely animated Prince of Egypt is an amalgam of Hollywood biblical epic, Broadway supermusical and nice Sunday school lesson."[33] James Berardinelli from Reelviews highly praised the film saying, "The animation in The Prince of Egypt is truly top-notch, and is easily a match for anything Disney has turned out in the last decade", and also wrote "this impressive achievement uncovers yet another chink in Disney's once-impregnable animation armor."[34] Liam Lacey of The Globe and Mail gave a somewhat negative review and wrote, "Prince of Egypt is spectacular but takes itself too seriously."[35] MovieGuide also reviewed the film favorably, saying that "The Prince of Egypt takes animated movies to a new level of entertainment. Magnificent art, music, story, and realization combine to make The Prince of Egypt one of the most entertaining masterpieces of all time."[36]

text: Censorship[edit]

text: The Prince of Egypt was banned in three countries where the population is predominantly Muslim: the Maldives, Malaysia, and Egypt on the grounds that the depiction in the media of Islamic prophets (which includes Moses) is forbidden in Islam. The movie was also banned in Indonesia, but was later released in Video CD Format. The Supreme Council of Islamic Affairs in the Maldives stated: "All prophets and messengers of God are revered in Islam, and therefore cannot be portrayed".[37][38] Following this ruling, the censor board banned the film in January 1999. In the same month, the Film Censorship Board of Malaysia banned the film "so as not to offend the country's majority Muslim population." The board's secretary said that the censor body ruled the film was "insensitive for religious and moral reasons".[39]

text: Accolades[edit]

text:
Award

Category

Recipient

Result

Academy Awards[40]

Best Original Musical or Comedy Score

Stephen Schwartz, Hans Zimmer

Nominated

Best Original Song

"When You Believe" (lyrics and music by Stephen Schwartz)

Won

Annie Awards[41]

Best Animated Feature

Penney Finkelman Cox and Sandra Rabins

Nominated

Individual Achievement in Directing

Brenda Chapman, Steve Hickner, and Simon Wells

Nominated

Individual Achievement in Storyboarding

Lorna Cook (Story supervisor)

Nominated

Individual Achievement in Effects Animation

Jamie Lloyd (Effects Lead — Burning Bush/Angel of Death)

Nominated

Individual Achievement in Voice Acting

Ralph Fiennes ("Rameses")

Nominated

Critics Choice Awards[42]

Best Animated Feature

Brenda Chapman, Steve Hickner, and Simon Wells

Won (tie with A Bug's Life)

Golden Globe Awards[43]

Best Original Score

Stephen Schwartz, Hans Zimmer

Nominated

Best Original Song

"When You Believe"

Nominated

Grammy Awards[44]

Best Song Written Specifically for a Motion Picture or Television

Nominated

Best Soundtrack Album

The Prince of Egypt: Music from the Motion Picture

Nominated

Satellite Award[45]

Best Animated or Mixed Media Feature

Nominated

Saturn Awards

Best Action/Adventure/Thriller Film

Nominated

Saturn Award for Best Music

Hans Zimmer

Nominated

text: The film is recognized by American Film Institute in these lists:

text:
2004: AFI's 100 Years...100 Songs:
"The Prince of Egypt (When You Believe)" – Nominated[46]

text: Prequel[edit]

text: In November 2000, DreamWorks Animation released Joseph: King of Dreams, a direct-to-video prequel based on the story of Joseph from the Book of Genesis. The project began during production of The Prince of Egypt, employing some of the same animation crew and featuring director Steve Hickner as an executive producer.[47][48]

text: Stage Musical[edit]

text: The Prince of Egypt debuted at TheatreWorks in Mountain View, California on October 14, 2017. The show had an international premiere on April 6, 2018 in Denmark at the Fredericia Teater.[49]


document_title: Renal sodium reabsorption

question_text: where does most reabsorption in the renal tubule occur

root

text: Renal sodium reabsorption

text: Proximal tubule[edit]

text: Most of the reabsorption (65%) occurs in the proximal tubule. In the latter part it is favoured by an electrochemical driving force, but initially it needs the cotransporter SGLT and the Na-H antiporter. Sodium passes along an electrochemical gradient (passive transport) from the lumen into the tubular cell, together with water and chloride which also diffuse passively. Water is reabsorbed to the same degree, resulting in the concentration in the end of the proximal tubule being the same as in the beginning. In other words, the reabsorption in the proximal tubule is isosmotic.

tag: p

text: Loop of Henle[edit]

text: Sodium is reabsorbed in the thick ascending limb of loop of Henle, by Na-K-2Cl symporter and Na-H antiporter. It goes against its chemical driving force, but the high electrical driving force renders the overall electrochemical driving force positive anyway, availing some sodium to diffuse passively either the transcellular or paracellular way..

text: Distal tubule[edit]

text: In the distal convoluted tubule sodium is transported against an electrochemical gradient by sodium-chloride symporters.

text: Collecting duct[edit]

text: The principal cells are the sodium-transporting cells in the collecting duct system.

text: Regulation[edit]

text: Although only a fragment of total reabsorption happens here, it is the main part of intervention. This is e.g. done by endogenous production of aldosterone, increasing reabsorption. Since the normal excretion rate of sodium is ~100mmoles/day, then a regulation of the absorption of still more than 1000 mmoles/day entering the collecting duct system has a substantial influence of the total sodium excreted.

text: Overview table[edit]

text:
Characteristics of Na+ reabsorption

Characteristic
proximal tubule
loop of Henle
Distal convoluted tubule
Collecting duct system

S1
S2
S3
descending limb
thin ascending limb
thick ascending limb
connecting tubule
initial collecting tubule
cortical collecting ducts
medullary collecting ducts

reabsorption (%)
67%[2]

25%[2]
5%[2]
3%[2]

reabsorption (mmoles/day)
~17,000[2]

~6,400[2]
~1,300[2]
~700[2]

Concentration (mM)
142[3]

142[3]

100[3]
70[3]

40[3]

electrical driving force (mV)
-3[3]

+3[3]

+15[3]
-5 to +5[3]

-40[3]

chemical driving force (mV)
0[3]

0[3]

-9[3]
-19[3]

-34[3]

electrochemical driving force (mV)
-3[3]

+3[3]

+6[3]
-24 to -14[3]

-74[3]

apical transport proteins
SGLT, Na-H antiporter[4]

(passively)
Na-K-2Cl symporter
(Na-H antiporter[4] and passively)
sodium-chloride symporter[4]

ENaC[4]

basolateral transport proteins
Na+/K+-ATPase[4]

Other reabsorption features
isosmotic

by principal cells, stimulated by aldosterone

tag: table


document_title: Grover

question_text: when did grover first appear on sesame street

text: Grover

text: Origins[edit]

text: A prototype version of Grover appeared on The Ed Sullivan Show in a Christmas Eve appearance in 1967. This puppet had greenish-brown fur and a red nose. He also had a raspier voice, and was played a bit more unkempt than Grover would later behave. The monster was referred to as "Gleep", a monster in Santa's workshop. He later made a cameo appearance in The Muppets On Puppets in 1968 with the Rock and Roll Monster. In 1969, clad in a necktie, he appeared in the Sesame Street Pitch Reel in the board room sequences. During the first season of Sesame Street, the character was nicknamed "Fuzzyface" or "The Hairy One", though neither would be used for his actual name. In his book The Tipping Point, author Malcolm Gladwell notes that the character "was used in promotional films for IBM."

text: In an appearance on The Ed Sullivan Show on May 31, 1970, the character acquired his present name and his appearance was changed to the more familiar puppet with blue fur and a pink nose. In this appearance, Kermit the Frog tried to sing "What Kind of Fool Am I?" (accompanying himself on piano), but Grover repeatedly interrupted him. The true Grover "officially" debuted in the second season of Sesame Street.

text: Appearances[edit]

text: Charlie's Restaurant[edit]

text: One of the more frequent sketch segments featuring Grover involves him taking a series of customer service jobs. One of his customers is always Mr. Johnson, a balding, mustachioed customer who invariably becomes frustrated at Grover's poor service and/or his (Grover's) insistence that he is serving him properly.

text: The first Grover-Mr. Johnson series of sketches, set at "Charlie's Restaurant," aired in the early 1970s; here, Grover is employed as a waiter and Mr. Johnson is his customer. The sketches followed the same basic premise: Mr. Johnson would order a menu item, Grover would serve the customer, a disagreement results (usually) as a result of Grover's mistakes, and Grover attempting (often, more than once) to correct the mistake with varying degrees of success. Under this backdrop, the sketches served to teach the childhood audience basic concepts such as same and different, big and little, hot and cold, the alphabet, following directions and patience, among other things.

text: Repeats of the "Charlie's Restaurant" series of sketches aired for many years on Sesame Street. In the years since, new Grover-Mr. Johnson sketches have been produced, with Grover taking other customer service jobs and Mr. Johnson as his hapless customer. Every time, Mr. Johnson recognizes Grover as "that waiter from Charlie's." Grover's jobs have ranged from that of a taxi driver and a photographer to a flight attendant and singing telegram artist. One sketch parodied the ABC television series Extreme Makeover: Home Edition in a segment where Grover began remodeling Mr. Johnson's home against his express wishes. In another one, Mr. Johnson is the only patron ,and Grover is the only actor, for a production of Spider-Monster: The Musical, a parody of the musical Spider-Man: Turn Off the Dark. The play is, of course, a complete calamity and finally comes crashing down on both of them.

text: Other segments[edit]

text: Grover also has an instructional persona who wears a cap and gown to provide educational context for simple, everyday things. His lessons are often wrong, leaving himself open to correction by a group of children or Muppets. This, combined with the failings of the Super Grover character, means that Grover can be very self-conscious and timid. He is often a source of slapstick humor and often accidentally injures himself.

text: Early in the series, Grover would often greet Kermit the Frog by running up to him and yelling, "Hey, froggy babeee!" and then giving him a hard slap on the back, which knocked him over.

text: Global Grover is a more recent series of segments, in which Grover hosts a trip to a foreign country to learn about their culture and customs.

text: In 2010, Grover starred in a parody of an Old Spice Commercial called "Smell Like a Monster" based on "The Man Your Man Could Smell Like", where a clam with "two tickets to the thing you love" bit his nose and he rode a cow rather than a horse.

text: Super Grover[edit]

text: Grover has a semi-secret superhero identity as the well-meaning but inept Super Grover, sometimes presented as the alter ego of Grover Kent, "ace doorknob salesman for Acme, Inc". Originally his superhero costume consisted of a pink cape and medieval knight's helmet, with a Superman-style crest on both the cape and his T-shirt, bearing a letter "G" on his chest instead of "S". During the 1970s and 1980s, Sesame Street ran a series of Super Grover sketches spoofing the classic Adventures of Superman series (in the opening of these, his name was hyphenated "Super-Grover"). An announcer (Jerry Nelson) introduced each episode with the lines:

text: "Presenting the further adventures of everybody's favorite hero. The man who is faster than lightning, stronger than steel, smarter than a speeding bullet. It's... Super Grover!"

text: With that, a fanfare sounds, Super Grover bursts through a paper wall bearing his crest, fruitlessly tries to move his helmet up off his eyes, and adds, "And I am cute, too!"

text:
Announcer: And now, on to our story.
Super Grover: Yes! On to our story!

text: From there, episodes followed a simple formula: Super Grover is flying somewhere over Metro City when he hears the cries of a Muppet child in some small trouble and immediately sails in to assist. The excited child is quickly disillusioned as Super Grover crash-lands nearby. From there, Grover continues to be enthusiastic but no help whatsoever, his "dramatic" feats of strength or speed serving only to kill time while the child solves the problem on their own and wanders off. By then, Grover's efforts have usually landed him in a comical predicament of his own.

text: Super Grover has appeared in the Sesame Street theatrical films Follow that Bird (1985) and The Adventures of Elmo in Grouchland (1999, where it's revealed he stretches his arms out and spins into his costume in homage to Wonder Woman), as well as the 1983 PBS special Don't Eat the Pictures.

text: For Sesame Street's 41st season in 2010, the character was revamped as Super Grover 2.0, who debuted on Late Night with Jimmy Fallon, flying in and crash-landing behind the chair where he was meant to sit. His new costume consists of a helmet reminiscent of a Spartan or Centurion, a red cape, and a black rubber vest resembling bike racing gear. Both the cape and the vest are adorned with his crest, now with a lightning bolt added behind the "G". Of course, the helmet has a hinged visor which still tends to fall over Grover's eyes. But now the tagline is Super Grover 2.0 - He Shows Up!

text: Mother[edit]

text: "Grover's Mommy" plays an integral but often unrecognized role on Sesame Street. She has been seen almost exclusively in print, including the many illustrated books starring Grover. She was also occasionally seen in photographs, as a photo puppet, such as on the cover of Volume 4 of The Sesame Street Treasury. Over the course of time, her appearance has fluctuated greatly.

text: Her earliest known appearance as a Muppet is a 1970s sketch in which Grover speaks to the audience about being afraid of the dark. At the end of the sketch, his mom (Frank Oz) enters his room to kiss him goodnight. Another early appearance (circa 1981) involves his mother (Kathryn Mullen) coming into the bathroom while Grover is telling the audience about how to take a bath.

text: She has recently appeared (performed by Stephanie D'Abruzzo) in a brief Elmo's World sequence (from the "Families" episode), with her son as his alter-ego Super Grover, as her own alter-ego, "Super-Mommy". Grover crashlands, screaming "Moooommy!" and his mom follows yelling "Soooonny!" crashing on top of him. They recover, acknowledge each other, and both faint.

text: Books[edit]

text: In the 1971 children's book The Monster at the End of This Book, Grover goes to great effort to keep the reader from turning the pages of the book, because there is a monster on the final page. Grover nails pages together and builds a brick wall to block access; at the end it is discovered that the monster at the end of the book is Grover himself, who is mortified ("Oh, I am so embarrassed..."). The late 90s saw a sequel to the book where Grover desperately tries to stop Elmo from reaching the end of the book, eventually directing him to leave the book and enter from the back. Therefore, when both of them reach the end, they wind up scaring each other.

text: Another popular children's book, Would You like to Play Hide & Seek in This Book with Lovable, Furry Old Grover?, had Grover trying different ways to hide from the reader, eventually getting upset and begging the reader to just say "no" he doesn't see him, even though he was just crouching down in a corner.

text: In 1974, Grover went on a learning expedition in Grover and The Everything In The Whole Wide World Museum. He tours rooms such as "The Long Thin Things You Can Write With Room", as well as "The Things That Make So Much Noise You Can't Think Room". Grover wanders through "The Things That are Light Room", returns a rock to "The Things That are Heavy Room", and just when he wonders whether it is possible to have a museum that holds everything in the whole wide world, he comes upon a door labeled "Everything Else", which opens to take him out into the world. As of 1996, Publishers Weekly ranked the book at seventy-nine on their list of best-selling children's paperbacks,[2] and Lou Harry of Indianapolis Business Journal included the book on his list of twelve examples of how muppets have qualified as quality entertainment.[3] It was written by Norman Stiles and Daniel Wilcox, and illustrated by Joe Mathieu.

text: The Adventures of Grover in Outer Space is a Sesame Street storybook featuring Grover that was published in 1984.[4] When Grover Moved to Sesame Street was published in 1985.[5] He was also featured in I Want a Hat Like That (1987, reprinted 1999).[6]

text: International[edit]

text: Sesame Street is modified for different national markets, and Grover is often renamed.

text:
In Gulf Cooperation Council , he is called Qarqor.
In Afghanistan, his name is Kajkoal,[7] meaning a bowl and refers to his mouth.
In Germany, he is Grobi, a diminutive of the German grob, meaning "rough" or "rude".
In Pakistan, he is Banka, meaning immature or youthful.
In Portugal, he is Gualter (Walter).
In Spain, he is called Coco, which is Spanish for coconut, referring to the shape of his head and mouth.
In Latin America and Puerto Rico, he is known as Archibaldo.
In Brazil, he is known as Arquibaldo, although in the 2007 versions maintains the name Grover.
In Norway, he is known as Gunnar and voiced by Harald Mæle.
In Egypt, he is called Gaafar.
In Indonesia, he is called Gatot.
In Israel, he is called Kruvi, which is a play on the word kruv ("cabbage").
In Turkey, he is known as Açıkgöz, meaning "leery".
In Czech Republic, he is called Bohouš.
In Poland, he is called Florek ("Sesame Street" only).

tag: ul


document_title: Mitochondrion

question_text: where is the mitochondria located in a cell

question_tokens: where is the mitochondria located in a cell

text: Mitochondrion

text: History

text: The first observations of intracellular structures that probably represented mitochondria were published in the 1840s.[19] Richard Altmann, in 1890, established them as cell organelles and called them "bioblasts".[19][20] The term "mitochondria" was coined by Carl Benda in 1898.[19][21] Leonor Michaelis discovered that Janus green can be used as a supravital stain for mitochondria in 1900. In 1904, Friedrich Meves, made the first recorded observation of mitochondria in plants in cells of the white waterlily, Nymphaea alba[19][22] and in 1908, along with Claudius Regaud, suggested that they contain proteins and lipids. Benjamin F. Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based on morphological observations.[19] In 1913, particles from extracts of guinea-pig liver were linked to respiration by Otto Heinrich Warburg, which he called "grana". Warburg and Heinrich Otto Wieland, who had also postulated a similar particle mechanism, disagreed on the chemical nature of the respiration. It was not until 1925, when David Keilin discovered cytochromes, that the respiratory chain was described.[19]

text: In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one oxygen atom can form two adenosine triphosphate (ATP) molecules, and, in 1941, the concept of the phosphate bonds of ATP being a form of energy in cellular metabolism was developed by Fritz Albert Lipmann. In the following years, the mechanism behind cellular respiration was further elaborated, although its link to the mitochondria was not known.[19] The introduction of tissue fractionation by Albert Claude allowed mitochondria to be isolated from other cell fractions and biochemical analysis to be conducted on them alone. In 1946, he concluded that cytochrome oxidase and other enzymes responsible for the respiratory chain were isolated to the mitchondria. Eugene Kennedy and Albert Lehninger discovered in 1948 that mitochondria are the site of oxidative phosphorylation in eukaryotes. Over time, the fractionation method was further developed, improving the quality of the mitochondria isolated, and other elements of cell respiration were determined to occur in the mitochondria.[19]

text: The first high-resolution electron micrographs appeared in 1952, replacing the Janus Green stains as the preferred way of visualising the mitochondria.[19] This led to a more detailed analysis of the structure of the mitochondria, including confirmation that they were surrounded by a membrane. It also showed a second membrane inside the mitochondria that folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied from cell to cell.

text: The popular term "powerhouse of the cell" was coined by Philip Siekevitz in 1957.[23]

text: In 1967, it was discovered that mitochondria contained ribosomes.[24] In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondrial DNA being completed in 1976.[19]

text: Origin and evolution

text: There are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotic hypothesis suggests that mitochondria were originally prokaryotic cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became endosymbionts living inside the eukaryote.[25] In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. Since mitochondria have many features in common with bacteria, the endosymbiotic hypothesis is more widely accepted.[25][26]

text: A mitochondrion contains DNA, which is organized as several copies of a single, circular chromosome. This mitochondrial chromosome contains genes for redox proteins, such as those of the respiratory chain. The CoRR hypothesis proposes that this co-location is required for redox regulation. The mitochondrial genome codes for some RNAs of ribosomes, and the 22 tRNAs necessary for the translation of messenger RNAs into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to the Rickettsia.[27][28] However, the exact relationship of the ancestor of mitochondria to the alphaproteobacteria and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial.[29]

text: A recent study[30] by researchers of the University of Hawaii at Manoa and the Oregon State University indicates that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria existing in most eukaryotic cells.

text:
Schematic phylogeny of Alphaproteobacteria, according to Ferla et al. (2013) [31]

Magnetococcidae

Magnetococcales

Magnetococcaceae

Magnetococcus marinus

Caulobacteridae

Rhodospirillales, Sphingomonadales, Rhodobacteraceae, Rhizobiales, etc.

Holosporales

Rickettsidae

Pelagibacterales

Pelagibacteraceae

Pelagibacter

subgroups Ib, II, IIIa, IIIb, IV and V

Proto-mitochondria

Anaplasmataceae

Ehrlichia

Anaplasma

Wolbachia

Neorickettsia

Midichloriaceae

Midichloria

Rickettsiaceae

Rickettsia

Robust 16S + 23S phylogeny of Rickettsidae from Ferla et al. [31]

text: The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[32] They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclear DNA.

text: The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.[33] The endosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. This symbiotic relationship probably developed 1.7[34] to 2[35] billion years ago.

text: A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: the microsporidians, metamonads, and archamoebae.[36] These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long-branch attraction—they are derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes).[1]

text: Monocercomonoides appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now.[37]

text: Structure

text: A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins.[13] The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion. They are:

text:
the outer mitochondrial membrane,
the intermembrane space (the space between the outer and inner membranes),
the inner mitochondrial membrane,
the cristae space (formed by infoldings of the inner membrane), and
the matrix (space within the inner membrane).

text: Mitochondria stripped of their outer membrane are called mitoplasts.

text: Outer membrane

text: The outer mitochondrial membrane, which encloses the entire organelle, is 60 to 75 angstroms (Å) thick. It has a protein-to-phospholipid ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral membrane proteins called porins. These porins form channels that allow molecules of 5000 daltons or less in molecular weight to freely diffuse from one side of the membrane to the other.[13] Larger proteins can enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, which then actively moves them across the membrane.[39] Mitochondrial pro-proteins are imported through specialised translocation complexes. The outer membrane also contains enzymes involved in such diverse activities as the elongation of fatty acids, oxidation of epinephrine, and the degradation of tryptophan. These enzymes include monoamine oxidase, rotenone-insensitive NADH-cytochrome c-reductase, kynurenine hydroxylase and fatty acid Co-A ligase. Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.[40] The mitochondrial outer membrane can associate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associated ER-membrane). This is important in the ER-mitochondria calcium signaling and is involved in the transfer of lipids between the ER and mitochondria. [41] Outside the outer membrane there are small (diameter: 60Å) particles named sub-units of Parson.

text: Intermembrane space

text: The intermembrane space is the space between the outer membrane and the inner membrane. It is also known as perimitochondrial space. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules, such as ions and sugars, in the intermembrane space is the same as in the cytosol.[13] However, large proteins must have a specific signaling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is cytochrome c.[40]

text: Inner membrane

text: The inner mitochondrial membrane contains proteins with five types of functions:[13]

text:
Those that perform the redox reactions of oxidative phosphorylation
ATP synthase, which generates ATP in the matrix
Specific transport proteins that regulate metabolite passage into and out of the matrix
Protein import machinery
Mitochondrial fusion and fission protein

text: It contains more than 151 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion.[13] In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in cow hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.[42] Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.[13] Unlike the outer membrane, the inner membrane doesn't contain porins, and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or via Oxa1.[39] In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes of the electron transport chain.

text: Cristae

text: The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. For typical liver mitochondria, the area of the inner membrane is about five times as large as the outer membrane. This ratio is variable and mitochondria from cells that have a greater demand for ATP, such as muscle cells, contain even more cristae. These folds are studded with small round bodies known as F1 particles or oxysomes. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic function.[43]

text: One recent mathematical modeling study has suggested that the optical properties of the cristae in filamentous mitochondria may affect the generation and propagation of light within the tissue.[44]

text: Matrix

text: The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.[13] The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.[13]

text: Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 genes: 22 tRNA, 2 rRNA, and 13 peptide genes.[45] The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus.

text: Mitochondria-associated ER membrane (MAM)

text: The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and homeostasis. Once considered a technical snag in cell fractionation techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER.[46] Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with fluorescence microscopy.[46] Such studies estimate that at the MAM, which may comprise up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10–25 nm and held together by protein tethering complexes.[46][47][48]

text: Purified MAM from subcellular fractionation has been shown to be enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca2+ signaling.[46][48] These hints of a prominent role for the MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant implications for mitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calcium signaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated 'powerhouses' hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate physical and functional coupling to the endomembrane system.

text: Phospholipid transfer

text: The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face and phosphatidylserine decarboxylase on the mitochondrial face.[49][50] Because mitochondria are dynamic organelles constantly undergoing fission and fusion events, they require a constant and well-regulated supply of phospholipids for membrane integrity.[51][52] But mitochondria are not only a destination for the phospholipids they finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism.[50][52]

text: Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles.[49] In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed bilayers.[52] Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP.[52] Instead, in yeast, it has been shown to be dependent on a multiprotein tethering structure termed the ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energy barrier for lipid flipping.[52][53]

text: The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. In particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway that leads to very-low-density lipoprotein, or VLDL, assembly and secretion.[50][54] The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

text: Calcium signaling

text: A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca2+ channels localized to the outer mitochondrial membrane seemed to fly in the face of this organelle's purported responsiveness to changes in intracellular Ca2+ flux.[46][55] But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca2+ microdomains at contact points that facilitate efficient Ca2+ transmission from the ER to the mitochondria.[46] Transmission occurs in response to so-called "Ca2+ puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca2+ channel.[46][47]

text: The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca2+ waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca2+ by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca2+ exposure, the MAM often serves as a firewall that essentially buffers Ca2+ puffs by acting as a sink into which free ions released into the cytosol can be funneled.[46][56][57] This Ca2+ tunneling occurs through the low-affinity Ca2+ receptor VDAC1, which recently has been shown to be physically tethered to the IP3R clusters on the ER membrane and enriched at the MAM.[46][47][58] The ability of mitochondria to serve as a Ca2+ sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process.[58] Normally, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.

text: But transmission of Ca2+ is not unidirectional; rather, it is a two-way street.[55] The properties of the Ca2+ pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca2+ by the MAM allows for spatio-temporal patterning of Ca2+ signaling because Ca2+ alters IP3R activity in a biphasic manner.[46] SERCA is likewise affected by mitochondrial feedback: uptake of Ca2+ by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca2+ for continued Ca2+ efflux at the MAM.[56][58] Thus, the MAM is not a passive buffer for Ca2+ puffs; rather it helps modulate further Ca2+ signaling through feedback loops that affect ER dynamics.

text: Regulating ER release of Ca2+ at the MAM is especially critical because only a certain window of Ca2+ uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca2+ signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.[59] However, once Ca2+ signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism.[46] Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca2+ filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli.[46] Given the need for such fine regulation of Ca2+ signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca2+ has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.[58]

text: Molecular basis for tethering

text: Recent advances in the identification of the tethers between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer.[52] However, a homologue of the ERMES complex has not yet been identified in mammalian cells. Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in fission and fusion events between individual mitochondria.[46] Glucose-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca2+ channels VDAC and IP3R for efficient Ca2+ transmission at the MAM.[46][47] Another potential tether is Sigma-1R, a non-opioid receptor whose stabilization of ER-resident IP3R may preserve communication at the MAM during the metabolic stress response.[60][61]

text: Perspective

text: The MAM is a critical signaling, metabolic, and trafficking hub in the cell that allows for the integration of ER and mitochondrial physiology. Coupling between these organelles is not simply structural but functional as well and critical for overall cellular physiology and homeostasis. The MAM thus offers a perspective on mitochondria that diverges from the traditional view of this organelle as a static, isolated unit appropriated for its metabolic capacity by the cell. Instead, this mitochondrial-ER interface emphasizes the integration of the mitochondria, the product of an endosymbiotic event, into diverse cellular processes.

text: Organization and distribution

text: Mitochondria (and related structures) are found in all eukaryotes (except one—the Oxymonad Monocercomonoides sp.).[2][62] Although commonly depicted as bean-like structures they form a highly dynamic network in the majority of cells where they constantly undergo fission and fusion. Mitochondria vary in number and location according to cell type. A single mitochondrion is often found in unicellular organisms. Conversely, numerous mitochondria are found in human liver cells, with about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume.[13] The population of all the mitochondria of a given cell constitutes the chondriome. The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential,[63] with differences arising from sources including uneven partitioning at cell divisions, leading to extrinsic differences in ATP levels and downstream cellular processes.[64] The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum.[13] Often, they form a complex 3D branching network inside the cell with the cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well:[65] different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages.[66] Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the endoplasmic reticulum.[67] Recent evidence suggests that vimentin, one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.[68]

text: Function

text: The most prominent roles of mitochondria are to produce the energy currency of the cell, ATP (i.e., phosphorylation of ADP), through respiration, and to regulate cellular metabolism.[14] The central set of reactions involved in ATP production are collectively known as the citric acid cycle, or the Krebs cycle. However, the mitochondrion has many other functions in addition to the production of ATP.

text: Energy conversion

text: A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glucose: pyruvate, and NADH, which are produced in the cytosol.[14] This type of cellular respiration known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic fermentation, a process that is independent of the mitochondria.[14] The production of ATP from glucose has an approximately 13-times higher yield during aerobic respiration compared to fermentation.[69] Recently it has been shown that plant mitochondria can produce a limited amount of ATP without oxygen by using the alternate substrate nitrite.[70] ATP crosses out through the inner membrane with the help of a specific protein, and across the outer membrane via porins. ADP returns via the same route.

text: Pyruvate and the citric acid cycle

text: Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix where they can either be oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH,[14] or they can be carboxylated (by pyruvate carboxylase) to form oxaloacetate. This latter reaction ”fills up” the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle’s capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in muscle) are suddenly increased by activity.[71]

text: In the citric acid cycle, all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence, the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell.[71]

text: Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO2 and water, with the energy thus released captured in the form of ATP.[71]

text: In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenic pathway, which converts lactate and de-aminated alanine into glucose,[14][71] under the influence of high levels of glucagon and/or epinephrine in the blood.[71] Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis.[71]

text: The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane as part of Complex II.[72] The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and a molecule of GTP (that is readily converted to an ATP).[14]

text: NADH and FADH2: the electron transport chain

text: The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis. Reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle.[14] Protein complexes in the inner membrane (NADH dehydrogenase (ubiquinone), cytochrome c reductase, and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide.[14] This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[73]

text: As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. The protons can return to the matrix through the ATP synthase complex, and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi).[14] This process is called chemiosmosis, and was first described by Peter Mitchell[74][75] who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.[76]

text: Heat production

text: Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons into the matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat.[14] The process is mediated by a proton channel called thermogenin, or UCP1.[77] Thermogenin is a 33 kDa protein first discovered in 1973.[78] Thermogenin is primarily found in brown adipose tissue, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.[77]

text: Storage of calcium ions

text: The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria can transiently store calcium, a contributing process for the cell's homeostasis of calcium.[79] [80] In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium.[81][82][83] The endoplasmic reticulum (ER) is the most significant storage site of calcium,[55] and there is a significant interplay between the mitochondrion and ER with regard to calcium.[84] The calcium is taken up into the matrix by the mitochondrial calcium uniporter on the inner mitochondrial membrane.[85] It is primarily driven by the mitochondrial membrane potential.[80] Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways.[85] This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a series of second messenger system proteins that can coordinate processes such as neurotransmitter release in nerve cells and release of hormones in endocrine cells.[86]

text: Ca2+ influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory bioenergetics by allowing the electrochemical potential across the membrane to transiently "pulse" from ΔΨ-dominated to pH-dominated, facilitating a reduction of oxidative stress.[87] In neurons, concomitant increases in cytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase, one of the key regulatory enzymes of the Kreb's cycle.[88]

text: Additional functions

text: Mitochondria play a central role in many other metabolic tasks, such as:

text:
Signaling through mitochondrial reactive oxygen species[89]
Regulation of the membrane potential[14]
Apoptosis-programmed cell death[90]
Calcium signaling (including calcium-evoked apoptosis)[91]
Regulation of cellular metabolism[92]
Certain heme synthesis reactions[93] (see also: porphyrin)
Steroid synthesis.[81]
Hormonal signaling [94] Mitochondria are sensitive and responsive to hormones, in part by the action of mitochondrial estrogen receptors (mtERs). These receptors have been found in various tissues and cell types, including brain [95] and heart [96]

text: Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in mitochondrial diseases.

text: Cellular proliferation regulation

text: The relationship between cellular proliferation and mitochondria has been investigated using cervical cancer HeLa cells. Tumor cells require an ample amount of ATP (Adenosine triphosphate) in order to synthesize bioactive compounds such as lipids, proteins, and nucleotides for rapid cell proliferation.[97] The majority of ATP in tumor cells is generated via the oxidative phosphorylation pathway (OxPhos).[98] Interference with OxPhos have shown to cause cell cycle arrest suggesting that mitochondria play a role in cell proliferation.[98] Mitochondrial ATP production is also vital for cell division in addition to other basic functions in the cell including the regulation of cell volume, solute concentration, and cellular architecture.[99][100][101] ATP levels differ at various stages of the cell cycle suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cycle.[102] ATP's role in the basic functions of the cell make the cell cycle sensitive to changes in the availability of mitochondrial derived ATP.[102] The variation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria play an important role in cell cycle regulation.[102] Although the specific mechanisms between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energy capability before committing to another round of cell division.[103]

text: Genome

text: Mitochondria contain their own genome, an indication that they are derived from bacteria through endosymbiosis (see Origin and evolution above). However, the ancestral endosymbiont genome has lost most of its genes so that the mitochondrial genome is one of the most reduced genomes across organisms.

text: The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.[104] It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV and V, 22 for mitochondrial tRNA (for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for rRNA.[104] One mitochondrion can contain two to ten copies of its DNA.[105]

text: As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts, which are cleaved and polyadenylated to yield mature mRNAs. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus and the corresponding proteins are imported into the mitochondrion.[45] The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. Most mitochondrial genomes are circular, although exceptions have been reported.[106] In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome;[45] however, introns have been observed in some eukaryotic mitochondrial DNA,[107] such as that of yeast[108] and protists,[109] including Dictyostelium discoideum.[110] Between protein-coding regions, tRNAs are present. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. Mitochondrial tRNA genes have different sequences from the nuclear tRNAs but lookalikes of mitochondrial tRNAs have been found in the nuclear chromosomes with high sequence similarity.[111]

text: In animals, the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long and has 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in the human body louse (Pediculus humanus). Instead, this mitochondrial genome is arranged in 18 minicircular chromosomes, each of which is 3–4 kb long and has one to three genes.[112] This pattern is also found in other sucking lice, but not in chewing lice. Recombination has been shown to occur between the minichromosomes. The reason for this difference is not known.

text: Alternative genetic code

text: While slight variations on the standard genetic code had been predicted earlier,[113] none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code.[114] However, the mitochondria of many other eukaryotes, including most plants, use the standard code.[115] Many slight variants have been discovered since,[116] including various alternative mitochondrial codes.[117] Further, the AUA, AUC, and AUU codons are all allowable start codons.

text:
Exceptions to the standard genetic code in mitochondria[13]

Organism
Codon
Standard
Mitochondria

Mammals
AGA, AGG
Arginine
Stop codon

Invertebrates
AGA, AGG
Arginine
Serine

Fungi
CUA
Leucine
Threonine

All of the above
AUA
Isoleucine
Methionine

UGA
Stop codon
Tryptophan

text: Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNA editing, which is common in mitochondria. In higher plants, it was thought that CGG encoded for tryptophan and not arginine; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the standard genetic code for tryptophan.[118] Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.[119]

text: Evolution and diversity

text: Mitochondrial genomes have far fewer genes than the bacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex II protein subunits.[104] This is thought to be relatively common over evolutionary time. A few organisms, such as the Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.[120] In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.[120]

text: Replication and inheritance

text: Mitochondria divide by binary fission, similar to bacterial cell division.[121] The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division is linked to the cell cycle. For example, a single mitochondrion may divide synchronously with the nucleus. This division and segregation process must be tightly controlled so that each daughter cell receives at least one mitochondrion. In other eukaryotes (in mammals for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. In such examples, and in contrast to the situation in many single celled eukaryotes, mitochondria are apparently randomly distributed to the daughter cells during the division of the cytoplasm. Understanding of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in pathologies associated with several disease conditions.[122]

text: The hypothesis of mitochondrial binary fission has relied on the visualization by fluorescence microscopy and conventional transmission electron microscopy (TEM). The resolution of fluorescence microscopy(~200 nm) is insufficient to distinguish structural details, such as double mitochondrial membrane in mitochondrial division or even to distinguish individual mitochondria when several are close together. Conventional TEM has also some technical limitations[which?] in verifying mitochondrial division. Cryo-electron tomography was recently used to visualize mitochondrial division in frozen hydrated intact cells. It revealed that mitochondria divide by budding.[123]

text: An individual's mitochondrial genes are not inherited by the same mechanism as nuclear genes. Typically, the mitochondria are inherited from one parent only. In humans, when an egg cell is fertilized by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually come from the egg only. The sperm's mitochondria enter the egg, but do not contribute genetic information to the embryo.[124] Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[125] The egg cell contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited only from mothers, a pattern known as maternal inheritance. This mode is seen in most organisms, including the majority of animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and yews.[126] For Mytilids, paternal inheritance only occurs within males of the species.[127][128][129] It has been suggested that it occurs at a very low level in humans.[130] There is a recent suggestion that mitochondria that shorten male lifespan stay in the system because they are inherited only through the mother. By contrast, natural selection weeds out mitochondria that reduce female survival as such mitochondria are less likely to be passed on to the next generation. Therefore, it is suggested that human females and female animals tend to live longer than males. The authors claim that this is a partial explanation.[131]

text: Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA.[105] For this reason, mitochondrial DNA is usually thought to reproduce by binary fission. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.[132] Further, evidence suggests that animal mitochondria can undergo recombination.[133] The data are a bit more controversial in humans, although indirect evidence of recombination exists.[134][135] If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations.

text: Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the inexorable accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated,[136][137][138] with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.[139]

text: Population genetic studies

text: The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology.[140] Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve.[141][142] This is often interpreted as strong support for a recent modern human expansion out of Africa.[143] Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for the lack of interbreeding between Neanderthals and anatomically modern humans.[144]

text: However, mitochondrial DNA reflects only the history of the females in a population and so may not represent the history of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such as the non-recombining region of the Y-chromosome.[143] In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.[145]

text: Recent measurements of the molecular clock for mitochondrial DNA[146] reported a value of 1 mutation every 7884 years dating back to the most recent common ancestor of humans and apes, which is consistent with estimates of mutation rates of autosomal DNA (10−8 per base per generation[147]).

text: Dysfunction and disease

text: Mitochondrial diseases

text: Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. Mitochondrial disorders often present themselves as neurological disorders, including autism.[12] They can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders.[148] Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy.[149] In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in mtDNA.[148]

text: In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease.[150] These diseases are inherited in a dominance relationship, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome.[148] Environmental influences may interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between pesticide exposure and the later onset of Parkinson's disease.[151][152] Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease,[153] Parkinson's disease, epilepsy, stroke, cardiovascular disease, chronic fatigue syndrome, retinitis pigmentosa, and diabetes mellitus.[154][155]

text: Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in Type 2 diabetics. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases uncoupling proteins (UCPs) and potentiate proton leakage through the adenine nucleotide translocator (ANT), the combination of which uncouples the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria is uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. The decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics.[156]

text: Possible relationships to aging

text: Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy electrons in the respiratory chain to form reactive oxygen species. This was thought to result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA (mtDNA).[157] Hypothesized links between aging and oxidative stress are not new and were proposed in 1956,[158] which was later refined into the mitochondrial free radical theory of aging.[159] A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress.

text: A number of changes can occur to mitochondria during the aging process.[160] Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.[161] However, mutated mtDNA can only be found in about 0.2% of very old cells.[162] Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of oxidative stress and neuronal death in Parkinson's disease.[163]

text: In popular culture

text: Madeleine L'Engle's 1973 science fantasy novel A Wind in the Door prominently features the mitochondria of main character Charles Wallace Murry, as being inhabited by creatures known as the farandolae. The novel also features other characters travelling inside one of Murry's mitochondria.

text: The 1995 horror fiction novel Parasite Eve by Hideaki Sena depicts mitochondria as having some consciousness and mind control abilities, attempting to use these to overtake eukaryotes as the dominant life form. This text was adapted into an eponymous film, video game, and video game sequel all involving a similar premise.

text: In the Star Wars franchise, microorganisms referred to as "midi-chlorians" give some characters the ability to sense and use the Force. George Lucas, director of the 1999 film Star Wars: Episode I – The Phantom Menace, in which midi-chlorians were introduced, described them as "a loose depiction of mitochondria".[164] The non-fictional Midichloria genus of bacteria was later named after the midi-chlorians of Star Wars.

text: As a result of the mitochondrion's prominence in modern science education, the phrase "mitochondria is [sic] the powerhouse of the cell" became a popular Internet meme.[165] The meme is used to imply that secondary education places an insufficient focus on life skills, compared to academic knowledge such as the role of the mitochondrion, which has been considered comparatively impractical.[166]


document_title: Ghost (Radical Face album)

question_text: what movie was welcome home by radical face in

text: Ghost (Radical Face album)

text:
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text:
Ghost

Studio album by Radical Face

Released
March 2007 (2007-03)

Genre
Alternative rock, Folk music

Length
47:46

Label
Morr Music

text: Ghost was the first studio album released by Radical Face in March 2007 on Morr Music.[1]

text: Ghost is a concept album based on the idea of houses retaining stories of what has happened in them. Each song is a story, some told from the house's point of view. Emeral Cooper cited an old house he lived in as one of the inspirations for Ghost. Most of his work on the album was done in an old tool shed behind his house. Cooper, Mark Hubbard, and Alex Kane collaborated with Ben Cooper for some tracks on the album.

text: Ghost has been compared to musical acts such as Pinback, The Mountain Goats, Sufjan Stevens, The Postal Service,[2] Gorky's Zygotic Mynci, Paul Simon,[3] and Animal Collective.[4]

text: "Welcome Home"[edit]

text: The song "Welcome Home" has been featured in advertisements and films, including a Nikon advertisement in several countries of Europe, an advertisement[5] for the 2011 Chevrolet Volt, and a promotional video for the University of Oregon that aired during the 2011 BCS Championship between Auburn and Oregon. The song appeared in the movie Humboldt County. It was featured in the Discovery Channel TV Series North America. The 2011 documentary film Forks Over Knives features the song over the ending credits. It is used in the climax of the film The Vicious Kind and featured in the film The Swiss Machine as speed alpine climber Ueli Steck ascends the Eiger. This film was part of the 2010 Reel Rock Tour. Steck's ascent to the tune of Radical Face's "Welcome Home" is featured in the Reel Rock Tour trailer. It was also used at the end of UK program Eddie Izzard: Marathon Man, toward the end of the first episode of the TV series Graceland, in the latter portion of the trailer for the 2012 documentary Mission to Lars and in a mountain bike short film of free-ride pro Andi Wittmann.[6][7] The song was heard in the fifth season of the popular British show, Skins, the second season of James May's Man Lab, and in the eighth episode of The Blacklist's first season. The song is listened to by a character in the opening scene of the pilot episode of the TV series The Returned. The song was featured during the credits of the 2016 movie Before I Wake. The song has been used as the official theme song for the Coastal Observation and Seabird Survey Team, Marine Debris Unit. The song reached number 58 in the UK Singles Chart in July 2012.[8]

text: Track listing[edit]

text:
No.
Title
Length

1.
"Asleep On The Train"
2:00

2.
"Welcome Home"
4:46

3.
"Let The River In"
5:05

4.
"Glory"
6:11

5.
"The Strangest Things"
4:24

6.
"Wrapped In Piano Strings"
3:36

7.
"Along The Road"
4:16

8.
"Haunted"
4:43

9.
"Winter Is Coming"
4:22

10.
"Sleepwalking"
4:41

11.
"Homesick"
3:42


document_title: Wisdom literature

question_text: what are the wisdom books in the bible

question_tokens: what are the wisdom books in the bible

text: Wisdom literature

text: Ancient Egyptian literature[edit]

text: This section needs expansion. You can help by adding to it. (July 2011)

text: In ancient Egyptian literature, wisdom literature belonged to the sebayt ("teaching") genre which flourished during the Middle Kingdom of Egypt and became canonical during the New Kingdom. Notable works of this genre include the Instructions of Kagemni, The Maxims of Ptahhotep, the Instructions of Amenemhat, and the Loyalist Teaching.

text: Biblical wisdom literature and Jewish texts[edit]

text: The most famous examples of wisdom literature are found in the Bible.[1][2]

text: Sapiential Books[edit]

text: The term "Sapiential Books" or "Books of Wisdom" is used in biblical studies to refer to a subset of the books of the Hebrew Bible in the Septuagint translation. There are seven of these books, namely the books of Job, Psalms, Proverbs, Ecclesiastes, the Song of Songs (Song of Solomon), the Book of Wisdom and Sirach (Ecclesiasticus). Not all the Psalms are usually regarded as belonging to the Wisdom tradition.[3]

text: In Judaism, the Books of Wisdom other than the Wisdom of Solomon and Sirach are regarded as part of the Ketuvim or "Writings". In Christianity, Job, Psalms, Proverbs, Song of Songs and Ecclesiastes are included in the Old Testament by all traditions, while Wisdom, and Sirach are regarded in some traditions as deuterocanonical works which are placed in the Apocrypha within the Anglican and Protestant Bible translations.[4]

text: The Sapiential Books are in the broad tradition of wisdom literature that was found widely in the Ancient Near East, including many religions other than Judaism.

text: Septuagint[edit]

text: The Greek noun sophia (σοφῐ́ᾱ, sophíā) is the translation of "wisdom" in the Greek Septuagint for Hebrew Ḥokmot (חכמות, khakhamút). Wisdom is a central topic in the "Sapiential" Books, i.e., Proverbs, Psalms, Job, Song of Songs, Ecclesiastes, Book of Wisdom, Wisdom of Sirach, and to some extent Baruch (the last three are Apocryphal / Deuterocanonical books of the Old Testament).

text: Classical texts[edit]

text: This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2018) (Learn how and when to remove this template message)

text:
Works and Days by Hesiod (c. 750-650 BC).
Nicomachean Ethics by Aristotle (384–322 BC).
Cato Maior de Senectute by Marcus Tullius Cicero (106-43 BC).
De Officiis by Marcus Tullius Cicero
Parallel Lives by Plutarch (46–120).
Meditations by Marcus Aurelius (121–180).
Maximes of François de La Rochefoucauld (1613–1680).