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Title: Mitochondrion  
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Subject: Chloroplast, Organelle, Chemiosmosis, Eukaryote, Cytosol
Collection: Cellular Respiration, Endosymbiotic Events, Organelles
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Two mitochondria from mammalian lung tissue displaying their matrix and membranes as shown by electron microscopy
Cell biology
Components of a typical animal cell:
  1. Nucleolus
  2. Nucleus
  3. Ribosome (little dots)
  4. Vesicle
  5. Rough endoplasmic reticulum
  6. Golgi apparatus (or "Golgi body")
  7. Cytoskeleton
  8. Smooth endoplasmic reticulum
  9. Mitochondrion
  10. Vacuole
  11. Cytosol (fluid that contains organelles)
  12. Lysosome
  13. Centrosome
  14. Cell membrane
Components of a typical mitochondrion

1 Outer membrane

1.1 Porin

2 Intermembrane space

2.1 Intracristal space
2.2 Peripheral space

3 Lamella

3.1 Inner membrane
3.11 Inner boundary membrane
3.12 Cristal membrane
3.2 Matrix
3.3 Cristæ

4 Mitochondrial DNA
5 Matrix granule
6 Ribosome
7 ATP synthase

The mitochondrion (plural mitochondria) is a eukaryotic cells (the cells that make up plants, animals, fungi, and many other forms of life).[1] The word mitochondrion comes from the Greek μίτος, mitos, i.e. "thread", and χονδρίον, chondrion, i.e. "granule".[2]

Mitochondria range from 0.5 to 1.0 micrometer (μm) in diameter. These structures are sometimes described as "the powerhouse of the cell" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.[3] In addition to supplying cellular energy, mitochondria are involved in other tasks such as signaling, cellular differentiation, cell death, as well as maintaining the control of the cell cycle and cell growth.[4] Mitochondria have been implicated in several human diseases, including mitochondrial disorders[5] and cardiac dysfunction,[6] and may play a role in the aging process. More recent research indicates that autism, especially severe autism, is correlated with mitochondrial defects.[7]

Several characteristics make mitochondria unique. The number of mitochondria in a cell can vary widely by outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix. Mitochondrial proteins vary depending on the tissue and the species. In humans, 615 distinct types of proteins have been identified from cardiac mitochondria,[10] whereas in rats, 940 proteins have been reported.[11] The mitochondrial proteome is thought to be dynamically regulated.[12] Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome. Further, its DNA shows substantial similarity to bacterial genomes.[13]


  • History 1
  • Structure 2
    • Outer membrane 2.1
    • Intermembrane space 2.2
    • Inner membrane 2.3
      • Cristae 2.3.1
    • Matrix 2.4
    • Mitochondria-associated ER membrane (MAM) 2.5
      • Phospholipid transfer 2.5.1
      • Calcium signaling 2.5.2
      • Molecular basis for tethering 2.5.3
      • Perspective 2.5.4
  • Organization and distribution 3
  • Function 4
    • Energy conversion 4.1
      • Pyruvate and the citric acid cycle 4.1.1
      • NADH and FADH2: the electron transport chain 4.1.2
      • Heat production 4.1.3
    • Storage of calcium ions 4.2
    • Additional functions 4.3
  • Cellular proliferation regulation 5
  • Origin 6
  • Genome 7
  • Replication and inheritance 8
  • Population genetic studies 9
  • Dysfunction and disease 10
    • Mitochondrial diseases 10.1
    • Possible relationships to aging 10.2
  • See also 11
  • References 12
  • External links 13


The first observations of intracellular structures that probably represent mitochondria were published in the 1840s.[14] [14] The term "mitochondria" itself was coined by Carl Benda in 1898.[14] Leonor Michaelis discovered that Janus green can be used as a supravital stain for mitochondria in 1900. Friedrich Meves, in 1904, made the first recorded observation of mitochondria in plants (Nymphaea alba)[14][15] 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.[14] 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.[14]

In 1939, experiments using minced muscle cells demonstrated that one oxygen atom can form two adenosine triphosphate molecules, and, in 1941, the concept of phosphate bonds 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.[14] 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. Over time, the fractionation method was tweaked, improving the quality of the mitochondria isolated, and other elements of cell respiration were determined to occur in the mitochondria.[14]

The first high-resolution micrographs appeared in 1952, replacing the Janus Green stains as the preferred way of visualising the mitochondria. 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.

The popular term "powerhouse of the cell" was coined by Philip Siekevitz in 1957.[16]

In 1967, it was discovered that mitochondria contained ribosomes. In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondria being completed in 1976.[14]


Mitochondrion ultrastructure (interactive diagram) A mitochondrion has a double membrane; the inner one contains its chemiosmotic apparatus and has deep grooves which increase its surface area. While commonly depicted as an "orange sausage with a blob inside of it" (like it is here), mitochondria can take many shapes[17] and their intermembrane space is quite thin.
Illustration depicting general mitochondrion structure

A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins.[8] The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion. They are:

  1. the outer mitochondrial membrane,
  2. the intermembrane space (the space between the outer and inner membranes),
  3. the inner mitochondrial membrane,
  4. the cristae space (formed by infoldings of the inner membrane), and
  5. the matrix (space within the inner membrane).

Mitochondria stripped of their outer membrane are called mitoplasts.

Outer membrane

The outer mitochondrial membrane, which encloses the entire phospholipid ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral proteins called porins. These porins form channels that allow molecules 5000 daltons or less in molecular weight to freely diffuse from one side of the membrane to the other.[8] 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.[18] Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.[19] 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 involved in the transfer of lipids between the ER and mitochondria.[20]

Intermembrane space

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 the cytosol.[8] 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.[19]

Inner membrane

The inner mitochondrial membrane contains proteins with five types of functions:[8]

  1. Those that perform the redox reactions of oxidative phosphorylation
  2. ATP synthase, which generates ATP in the matrix
  3. Specific transport proteins that regulate metabolite passage into and out of the matrix
  4. Protein import machinery.
  5. Mitochondria fusion and fission protein.

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.[8] 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.[21] Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.[8] 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.[18] In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes of the electron transport chain.


Cross-sectional image of cristae in rat liver mitochondrion to demonstrate the likely 3D structure and relationship to the inner membrane

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.[22]

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.[23]


The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.[8] 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.[8]

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 total genes: 22 tRNA, 2 rRNA, and 13 peptide genes.[24] 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.

Mitochondria-associated ER membrane (MAM)

The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and fluorescence microscopy.[25] 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.[25][26][27]

Purified MAM from subcellular fractionation has shown to be enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca2+ signaling.[25][27] 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.

Phospholipid transfer

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.[28][29] Because mitochondria are dynamic organelles constantly undergoing

External links

  1. ^ a b Henze K, Martin W; Martin, William (2003). "Evolutionary biology: essence of mitochondria". Nature 426 (6963): 127–8.  
  2. ^ "mitochondria".  
  3. ^ Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life. Boston, Massachusetts: Pearson Prentice Hall.  
  4. ^ McBride HM, Neuspiel M, Wasiak S (2006). "Mitochondria: more than just a powerhouse". Curr. Biol. 16 (14): R551–60.  
  5. ^ Gardner A, Boles RG (2005). "Is a "Mitochondrial Psychiatry" in the Future? A Review". Curr. Psychiatry Review 1 (3): 255–271.  
  6. ^ Lesnefsky EJ, Moghaddas S, Tandler B, Kerner B, Hoppel CL (June 2001). "Mitochondrial dysfunction in cardiac disease: ischemia—reperfusion, aging, and heart failure".  
  7. ^ a b Study Confirms Mitochondrial Deficits in Children with Autism. May 2014
  8. ^ a b c d e f g h i j k l Alberts, Bruce; Alexander Johnson; Julian Lewis; Martin Raff; Keith Roberts; Peter Walter (1994). Molecular Biology of the Cell. New York: Garland Publishing Inc.  
  9. ^ a b c d e f g h i j k Voet, Donald; Judith G. Voet; Charlotte W. Pratt (2006). Fundamentals of Biochemistry, 2nd Edition. John Wiley and Sons, Inc. p. 547.  
  10. ^ Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS (March 2003). "Characterization of the human heart mitochondrial proteome". Nat Biotechnol. 21 (3): 281–6.  
  11. ^ Zhang J, Li X, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Liem DA, Yang J, Korge P, Honda H, Weiss JN, Apweiler R, Ping P (2008). "Systematic Characterization of the Murine Mitochondrial Proteome Using Functionally Validated Cardiac Mitochondria". Proteomics 8 (8): 1564–1575.  
  12. ^ Zhang J, Liem DA, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Yang J, Korge P, Drews O, Maclellan WR, Honda H, Weiss JN, Apweiler R, Ping P (2008). "Altered Proteome Biology of Cardiac Mitochondria Under Stress Conditions". J. Proteome Res 7 (6): 2204–14.  
  13. ^ Andersson SG, Karlberg O, Canbäck B, Kurland CG (January 2003). "On the origin of mitochondria: a genomics perspective". Philosophical Transactions of the Royal Society B 358 (1429): 165–77; discussion 177–9.  
  14. ^ a b c d e f g h i Ernster L, Schatz G (1981). "Mitochondria: a historical review". The Journal of Cell Biology 91 (3 Pt 2): 227s–255s.  
  15. ^ Ernster's citation Meves, Friedrich (May 1908). "Die Chondriosomen als Träger erblicher Anlagen. Cytologische Studien am Hühnerembryo". Archiv für mikroskopische Anatomie 72 (1): 816–867.  , with confirmation of Nymphaea alba
  16. ^ Siekevitz P (1957). "Powerhouse of the cell".  
  17. ^ "Mitochondrion – much more than an energy converter". British Society for Cell Biology. Retrieved 19 August 2013. 
  18. ^ a b Herrmann JM, Neupert W (April 2000). "Protein transport into mitochondria". Current Opinion in Microbiology 3 (2): 210–214.  
  19. ^ a b Chipuk JE, Bouchier-Hayes L, Green DR (2006). "Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario". Cell Death and Differentiation 13 (8): 1396–1402.  
  20. ^ Hayashi T, Rizzuto R, Hajnoczky G, Su TP (February 2009). "MAM: more than just a housekeeper". Trends Cell Biol. 19 (2): 81–8.  
  21. ^ McMillin JB, Dowhan W (December 2002). "Cardiolipin and apoptosis". Biochim. Et Biophys. Acta 1585 (2–3): 97–107.  
  22. ^ Mannella CA (2006). "Structure and dynamics of the mitochondrial inner membrane cristae". Biochimica et Biophysica Acta 1763 (5–6): 542–548.  
  23. ^ Thar, R.; Kühl, Michael (2004). "Propagation of electromagetic radiation in mitochondria?" (PDF).  
  24. ^ a b c Anderson S, Bankier AT, Barrell BG, de-Bruijn MHL, Coulson AR, et al. (1981). "Sequence and organization of the human mitochondrial genome". Nature 290 (5806): 427–465.  
  25. ^ a b c d e f g h i j k l m n Rizzuto, R.; Marchi, Saverio; Bonora, Massimo; Aguiari, Paola; Bononi, Angela; De Stefani, Diego; Giorgi, Carlotta; Leo, Sara; Rimessi, Alessandro (2009). transfer from the ER to mitochondria: when, how and why"2+"Ca. Biochim Biophys Acta 1787 (11): 1342–51.  
  26. ^ a b c d Hayashi, T.; Rizzuto, Rosario; Hajnoczky, Gyorgy; Su, Tsung-Ping (2009). "MAM: more than just a housekeeper". Trends Cell Biol. 19 (2): 81–88.  
  27. ^ a b de Brito, OM et al. (2010). "An intimate liaison: spatial organization of the endoplasmic reticulum–mitochondria relationship". EMBO J. 29 (16): 2715–2723.  
  28. ^ a b Vance, JE. et al.; Shiao, YJ (1996). "Intracellular trafficking of phospholipids: import of phosphatidylserine into mitochondria". Anticancer Research 16 (3B): 1333–9.  
  29. ^ a b c Lebiedzinska, M.; Szabadkai, György; Jones, Aleck W.E.; Duszynski, Jerzy; Wieckowski, Mariusz R. (2009). "Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles". Int J Biochem Cell Biol 41 (10): 1805–16.  
  30. ^ Twig, G.; Elorza, Alvaro; Molina, Anthony J A; Mohamed, Hibo; Wikstrom, Jakob D; Walzer, Gil; Stiles, Linsey; Haigh, Sarah E; Katz, Steve (2008). "Fission and selective fusion govern mitochondrial segregation and elimination by autophagy". The EMBO Journal 27 (2): 433–446.  
  31. ^ a b c d e f Osman, C.; Voelker, D. R.; Langer, T. (2011). "Making heads or tails of phospholipids in mitochondria". J Cell Biol 192 (1): 7–16.  
  32. ^ Kornmann, B.; Currie, E.; Collins, S. R.; Schuldiner, M.; Nunnari, J.; Weissman, J. S.; Walter, P. (2009). "An ER-Mitochondria Tethering Complex Revealed by a Synthetic Biology Screen". Science 325 (24): 477–481.  
  33. ^ Rusinol, A. E.; Cui, Z; Chen, MH; Vance, JE (1994). "A Unique Mitochondria-associated Membrane Fraction from Rat Liver Has a High Capacity for Lipid Synthesis and Contains Pre-Golgi Secretory Proteins Including Nascent Lipoprotein". J Biol Chem 269 (44): 27494–27502.  
  34. ^ a b Kopach, O.; Kruglikov, Illya; Pivneva, Tatyana; Voitenko, Nana; Fedirko, Nataliya (2008). "Functional coupling between ryanodine receptors, mitochondria and Ca2+ ATPases in rat submandibular acinar cells".  
  35. ^ Csordas, G.; Hajnóczky, G (2001). "Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria". Cell Calcium. 29 (4): 249–262.  
  36. ^ a b c d Decuypere, J. P.; Monaco, Giovanni; Bultynck, Geert; Missiaen, Ludwig; De Smedt, Humbert; Parys, Jan B. (2011). "The IP3 receptor–mitochondria connection in apoptosis and autophagy". Biochim Biophys Acta 1813 (5): 1003–13.  
  37. ^ Hajnoczky, G.; Csordás, G; Yi, M (2011). "Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria". Cell Calcium 32 (5–6): 363–377.  
  38. ^ Marriott, KS; Prasad, M; Thapliyal, V; Bose, HS (December 2012). "σ-1 Receptor at the Mitochondrial-Associated Endoplasmic Reticulum Membrane Is Responsible for Mitochondrial Metabolic Regulation". The Journal of Pharmacology and Experimental Therapeutics 343 (3): 578–86.  
  39. ^ Hayashi, T; Su, TP (Nov 2, 2007). "Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival". Cell 131 (3): 596–610.  
  40. ^ The eukaryote  
  41. ^ das Neves RP, Jones NS, Andreu L, Gupta R, Enver T, Iborra FJ (2010). Weissman, Jonathan S, ed. "Connecting Variability in Global Transcription Rate to Mitochondrial Variability". PLOS Biology 8 (12): e1000560.  
  42. ^ Johnston IG, Gaal B, das Neves RP, Enver T, Iborra FJ, Jones NS (2012). Haugh, Jason M, ed. "Mitochondrial Variability as a Source of Extrinsic Cellular Noise". PLOS Computational Biology 8 (3): e1002416.  
  43. ^ Rappaport L, Oliviero P, Samuel JL (1998). "Cytoskeleton and mitochondrial morphology and function". Mol and Cell Biochem. 184: 101–105.  
  44. ^ Soltys B. J.; Gupta R. S. (1992). "Interrelationships of endoplasmic reticulum, mitochondria, intermediate filaments, and microtubules—a quadruple fluorescence labeling study". Biochem Cell Biol. 70 (10–11): 1174–86.  
  45. ^ Tang HL, Lung HL, Wu KC, Le AP, Tang HM, Fung MC (2007). "Vimentin supports mitochondrial morphology and organization". Biochemical J 410 (1): 141–6.  
  46. ^ Rich PR (2003). "The molecular machinery of Keilin's respiratory chain". Biochem. Soc. Trans. 31 (Pt 6): 1095–105.  
  47. ^ Stoimenova M, Igamberdiev AU, Gupta KJ, Hill RD (July 2007). "Nitrite-driven anaerobic ATP synthesis in barley and rice root mitochondria". Planta 226 (2): 465–74.  
  48. ^ King A, Selak MA, Gottlieb E (2006). "Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer". Oncogene 25 (34): 4675–4682.  
  49. ^ Huang, K.; K. G. Manton (2004). "The role of oxidative damage in mitochondria during aging: A review". Frontiers in Bioscience 9: 1100–1117.  
  50. ^ Mitchell P, Moyle J (1967-01-14). "Chemiosmotic hypothesis of oxidative phosphorylation". Nature 213 (5072): 137–9.  
  51. ^ Mitchell P (1967-06-24). "Proton current flow in mitochondrial systems". Nature 25 (5095): 1327–8.  
  52. ^ Nobel Foundation. "Chemistry 1997". Retrieved 2007-12-16. 
  53. ^ a b Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F (November 2005). "Thermoregulation: What Role for UCPs in Mammals and Birds?". Bioscience Reports 25 (3–4): 227–249.  
  54. ^ Nicholls DG, Lindberg O (1973). "Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities". Eur. J. Biochem. 37 (3): 523–30.  
  55. ^ a b Editor-in-chief, George J. Siegel; editors, Bernard W. Agranoff... [et al.]; illustrations by Lorie M. Gavulic (1999). Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD, ed. Basic Neurochemistry (6 ed.). Lippincott Williams & Wilkins.  
  56. ^ a b Rossier MF (2006). "T channels and steroid biosynthesis: in search of a link with mitochondria". Cell Calcium. 40 (2): 155–64.  
  57. ^ Brighton, Carl T.; Hunt, Robert M. (1974). "Mitochondrial calcium and its role in calcification". Clinical Orthopaedics and Related Research 100 (100): 406–416.  
  58. ^ Brighton, Carl T.; Hunt, Robert M. (1978). "The role of mitochondria in growth plate calcification as demonstrated in a rachitic model". Journal of Bone and Joint Surgery 60 (5): 630–639.  
  59. ^ Pizzo P, Pozzan T (2007). "Mitochondria–endoplasmic reticulum choreography: structure and signaling dynamics". Trends Cell Biol. 17 (10): 511–517.  
  60. ^ a b Miller RJ (1998). "Mitochondria – the kraken wakes!". Trends in Neurosci. 21 (3): 95–97.  
  61. ^ Schwarzlander M, Logan DC, Johnston IG, Jones NS, Meyer AJ, Fricker MD, Sweetlove LJ (2012). "Pulsing of Membrane Potential in Individual Mitochondria: A Stress-Induced Mechanism to Regulate Respiratory Bioenergetics in Arabidopsis". Plant Cell 24 (3): 1188–201.  
  62. ^ Ivannikov, M. et al. (2013). Levels and Their Effects on Energy Metabolism in Drosophila Motor Nerve Terminals"2+"Mitochondrial Free Ca.  
  63. ^ Li X, Fang P, Mai J, "et al." (2013). "Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers". J Hematol Oncol. 6 (19): 19.  
  64. ^ Green DR (September 1998). "Apoptotic pathways: the roads to ruin". Cell 94 (6): 695–8.  
  65. ^ Hajnóczky G, Csordás G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, Yi M (2006). uptake in apoptosis"2+"Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca. Cell Calcium 40 (5–6): 553–60.  
  66. ^ McBride HM, Neuspiel M, Wasiak S (2006). "Mitochondria: more than just a powerhouse". Curr Biol. 16 (14): R551–60.  
  67. ^ Oh-hama T (1997). "Evolutionary consideration on 5-aminolevulinate synthase in nature". Orig Life Evol Biosph. 27 (4): 405–12.  
  68. ^ Klinge, Carolyn (2008). "Estrogenic Control of Mitochondrial Function and Biogenesis". J Cell Biochem 105 (6): 1342–1351.  
  69. ^ Álvarez-Delgado, Carolina (2010). "Different expression of alpha and beta mitochondrial estrogen receptors in the aging rat brain: interaction with respiratory complex V.". Experimental Gerontology 45 (7–8): 580–585.  
  70. ^ Pavón, Natalia (2012). "Sexual hormones: effects on cardiac and mitochondrial activity after ischemia-reperfusion in adult rats. Gender difference.". J Steroid Biochem Mol Biol 132 (1–2): 135–146.  
  71. ^ Weinberg, Frank; Chandel, Navdeep S. (2009). "Mitochondrial Metabolism and Cancer". Annals of the New York Academy of Sciences 1177 (1): 66–73.  
  72. ^ a b Moreno-Sánchez, Rafael; Rodríguez-Enríquez, Sara; Marín-Hernández, Alvaro; Saavedra, Emma (2007). "Energy metabolism in tumor cells". FEBS Journal 274 (6): 1393–1418.  
  73. ^ Pedersen, Peter L. (1994). "ATP Synthase: The machine that makes ATP". Current Biology 4 (12): 1138–1141.  
  74. ^ Pattappa, Girish; Heywood, Hannah K.; de Bruijn, Joost D.; Lee, David A. (2011). "The metabolism of human mesenchymal stem cells during proliferation and differentiation". Journal of Cellular Physiology 226 (10): 2562–2570.  
  75. ^ Agarwal, Bhawana (2011). "A role for anions in ATP synthesis and its molecular mechanistic interpretation". Journal of Bioenergetics and Biomembranes 43 (3): 299–310.  
  76. ^ a b c Sweet, S.; Singh, G. (1999). "Changes in mitochondrial mass, membrane potential, and cellular adenosine triphosphate content during the cell cycle of human leukemic (HL-60) cells". Journal of Cellular Physiology 180 (1): 91–96.  
  77. ^ McBride, Heidi M.; Neuspiel, Margaret; Wasiak, Sylwia (2006). "Mitochondria: More Than Just a Powerhouse". Current Biology 16 (14): R551–R560.  
  78. ^ William F. Martin and Miklós Müller "Origin of mitochondria and hydrogenosomes", Springer Verlag, Heidelberg 2007.
  79. ^ Emelyanov VV (2003). "Mitochondrial connection to the origin of the eukaryotic cell". Eu J Biochem. 270 (8): 1599–1618.  
  80. ^ Gray MW, Burger G, Lang BF (March 1999). "Mitochondrial evolution". Science 283 (5407): 1476–81.  
  81. ^ Thrash, J. Cameron et al. (2011). "Phylogenomic evidence for a common ancestor of mitochondria and the SAR11 clade". Scientific Reports 1.  
  82. ^ Williams, K. P.; Sobral, B. W.; Dickerman, A. W. (2007). "A Robust Species Tree for the Alphaproteobacteria". Journal of Bacteriology 189 (13): 4578–4586.  
  83. ^ O'Brien TW (2003). "Properties of human mitochondrial ribosomes". IUBMB Life 55 (9): 505–13.  
  84. ^ Lynn Sagan (1967). "On the origin of mitosing cells".  
  85. ^ Emelyanov VV (2001). "Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria". Biosci. Rep. 21 (1): 1–17.  
  86. ^ Feng D-F, Cho G, Doolittle RF (1997). "Determining divergence times with a protein clock: Update and reevaluation". Proc. Natl. Acad. Sci. 94 (24): 13028–13033.  
  87. ^ Cavalier-Smith T (1991). "Archamoebae: the ancestral eukaryotes?". Biosystems 25 (1–2): 25–38.  
  88. ^ a b c Chan DC (2006-06-30). "Mitochondria: Dynamic Organelles in Disease, Aging, and Development". Cell 125 (7): 1241–1252.  
  89. ^ a b Wiesner RJ, Ruegg JC, Morano I (1992). "Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues". Biochim Biophys Acta 183 (2): 553–559.  
  90. ^ Fukuhara H, Sor F, Drissi R, Dinouël N, Miyakawa I, Rousset, and Viola AM (1993). "Linear mitochondrial DNAs of yeasts: frequency of occurrence and general features". Mol Cell Biol. 13 (4): 2309–2314.  
  91. ^ Bernardi G (1978). "Intervening sequences in the mitochondrial genome". Nature 276 (5688): 558–559.  
  92. ^ Hebbar SK, Belcher SM, Perlman PS (April 1992). "A maturase-encoding group IIA intron of yeast mitochondria self-splices in vitro". Nucleic Acids Research 20 (7): 1747–54.  
  93. ^ Gray MW, Lang BF, Cedergren R, Golding GB, Lemieux C, Sankoff D, et al. (1998). "Genome structure and gene content in protist mitochondrial DNAs". Nucleic Acids Research 26 (4): 865–878.  
  94. ^ Gray MW, Lang BF, Burger G (2004). "Mitochondria of protists". Ann Rev of Genetics 38: 477–524.  
  95. ^ Telonis Aristeidis G. et al. (2014). "Nuclear and Mitochondrial tRNA-lookalikes in the Human Genome". Frontiers in Genetics 5: 00344.  
  96. ^ Shao R, Kirkness EF, Barker SC (March 2009). "The single mitochondrial chromosome typical of animals has evolved into 18 minichromosomes in the human body louse, Pediculus humanus". Genome Res. 19 (5): 904–12.  
  97. ^ Crick, F. H. C. and Orgel, L. E. (1973). "Directed panspermia". Icarus 19: 341–346.   Further discussion.
  98. ^ Barrell BG, Bankier AT, Drouin J (1979). "A different genetic code in human mitochondria". Nature 282 (5735): 189–194.  
  99. ^ Mitochondrial Genetic Code in Taxonomy Tree. NCBI
  100. ^ Elzanowski, Andrzej and Ostell, Jim. The Genetic Codes. NCBI
  101. ^ Jukes TH, Osawa S (1990). "The genetic code in mitochondria and chloroplasts". Experientia 46 (11–12): 1117–26.  
  102. ^ Hiesel R, Wissinger B, Schuster W, Brennicke A (2006). "RNA editing in plant mitochondria". Science 246 (4937): 1632–4.  
  103. ^ Abascal F, Posada D, Knight RD, Zardoya R (2006). "Parallel Evolution of the Genetic Code in Arthropod Mitochondrial Genomes". PLOS Biology 4 (5): 0711–0718.  
  104. ^ a b Henriquez FL, Richards TA, Roberts F, McLeod R, Roberts CW (2005). "The unusual mitochondrial compartment of Cryptosporidium parvum". Trends Parasitol. 21 (2): 68–74.  
  105. ^ Pfeiffer, Ronald F. (2012). Parkinson's Disease. CRC Press. p. 583. 
  106. ^ Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C (2010). "New insights into the role of mitochondria in aging: mitochondrial dynamics and more". J. Cell. Sci. 123 (15): 2533–42.  
  107. ^ Hu GB (2014). "Whole Cell Cryo-electron tomography suggest mitochondria divide by budding". Microsc and microanal: 1–8.  
  108. ^ Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization," Kimball's Biology Pages (based on Biology, 6th ed., 1996)
  109. ^ Sutovsky, P., et al. (1999). "Ubiquitin tag for sperm mitochondria".   Discussed in Science News.
  110. ^ Mogensen HL (1996). "The Hows and Whys of Cytoplasmic Inheritance in Seed Plants". American Journal of Botany 83 (3): 383–404.  
  111. ^ Zouros E (December 2000). "The exceptional mitochondrial DNA system of the mussel family Mytilidae". Genes Genet. Syst. 75 (6): 313–8.  
  112. ^ Sutherland B, Stewart D, Kenchington ER, Zouros E (1 January 1998). "The fate of paternal mitochondrial DNA in developing female mussels, Mytilus edulis: implications for the mechanism of doubly uniparental inheritance of mitochondrial DNA". Genetics 148 (1): 341–7.  
  113. ^ Species Group(Mytilus edulis)Male and Female Mitochondrial DNA Lineages in the Blue Mussel by Donald T. Stewart, Carlos Saavedra, Rebecca R. Stanwood, Amy 0. Ball, and Eleftherios Zouros
  114. ^ Johns, D. R. (2003). "Paternal transmission of mitochondrial DNA is (fortunately) rare". Annals of Neurology 54 (4): 422–4.  
  115. ^ Fruit flies offer DNA clue to why women live longer. BBC. 2 August 2012
  116. ^ Thyagarajan B, Padua RA, Campbell C (1996). "Mammalian mitochondria possess homologous DNA recombination activity". J. Biol. Chem. 271 (44): 27536–27543.  
  117. ^ Lunt DB, Hyman BC (15 May 1997). "Animal mitochondrial DNA recombination". Nature 387 (6630): 247.  
  118. ^ Eyre-Walker A, Smith NH, Maynard Smith J (1999-03-07). "How clonal are human mitochondria?".  
  119. ^ Awadalla P, Eyre-Walker A, Maynard Smith J (1999). "Linkage Disequilibrium and Recombination in Hominid Mitochondrial DNA". Science 286 (5449): 2524–2525.  
  120. ^ Castro JA, Picornell A, Ramon M (1998). "Mitochondrial DNA: a tool for populational genetics studies". Int Microbiol. 1 (4): 327–32.  
  121. ^ Cann RL, Stoneking M, Wilson AC (January 1987). "Mitochondrial DNA and human evolution". Nature 325 (6099): 31–36.  
  122. ^ Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (2006). "Harvesting the fruit of the human mtDNA tree". Trends Genet. 22 (6): 339–45.  
  123. ^ a b Garrigan D, Hammer MF (2006). "Reconstructing human origins in the genomic era". Nature Reviews Genetics 7 (9): 669–80.  
  124. ^ Krings M, Stone A, Schmitz RW, Krainitzki H, Stoneking M, Pääbo S (1997). "Neandertal DNA sequences and the origin of modern humans". Cell 90 (1): 19–30.  
  125. ^ Harding RM, Fullerton SM, Griffiths RC, Bond J, Cox MJ, Schneider JA, Moulin DS, Clegg JB (April 1997). "Archaic African and Asian lineages in the genetic ancestry of modern humans". American Journal of Human Genetics 60 (4): 772–89.  
  126. ^ Soares, et al. (June 2009). "Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock". Am J Hum Genet 84 (6): 740–759.  
  127. ^ Michael W. Nachman and Susan L. Crowell Estimate of the Mutation Rate per Nucleotide in Humans Genetics, Vol. 156, 297–304, September 2000
  128. ^ a b c Zeviani M, Di Donato S (2004). "Mitochondrial disorders". Brain 127 (Pt 10): 2153–2172.  
  129. ^ Taylor RW, Turnbull DM (2005). "MITOCHONDRIAL DNA MUTATIONS IN HUMAN DISEASE". Nature Reviews Genetics 6 (5): 389–402.  
  130. ^ Chinnery PF, Schon EA (2003). "Mitochondria". J. Neurol. Neurosurg. Psychiatr. 74 (9): 1188–99.  
  131. ^ Sherer TB, Betarbet R, Greenamyre JT (2002). "Environment, mitochondria, and Parkinson's disease".  
  132. ^ Gomez C, Bandez MJ, Navarro A (2007). "Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome". Front. Biosci. 12: 1079–93.  
  133. ^ Lim Y. A.; Rhein, Virginie; Baysang, Ginette; Meier, Fides; Poljak, Anne; j. Raftery, Mark; Guilhaus, Michael; Ittner, Lars M.; Eckert, Anne (2010). "Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction". Proteomics 10 (8): 1621–33.  
  134. ^ Schapira AH (2006). "Mitochondrial disease". Lancet 368 (9529): 70–82.  
  135. ^ Pieczenik SR, Neustadt J (2007). "Mitochondrial dysfunction and molecular pathways of disease". Exp. Mol. Pathol. 83 (1): 84–92.  
  136. ^ Bugger H, Abel ED (2010). "Mitochondria in the diabetic heart". Cardiovascular Research 88 (2): 229–240.  
  137. ^ Richter C, Park J, Ames BN (September 1988). "Normal oxidative damage to mitochondrial and nuclear DNA is extensive". PNAS 85 (17): 6465–6467.  
  138. ^ Harman D (1956). "Aging: a theory based on free radical and radiation chemistry". J. Gerontol. 11 (3): 298–300.  
  139. ^ Harman, D (1972). "A biologic clock: the mitochondria?". Journal of the American Geriatrics Society 20 (4): 145–147.  
  140. ^ "Mitochondria and Aging". 
  141. ^ Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S (1994). "Decline with age of the respiratory chain activity in human skeletal muscle". Biochim. Biophys. Acta 1226 (1): 73–82.  
  142. ^ de Grey, Aubrey (2004). "Mitochondrial Mutations in Mammalian Aging: An Over-Hasty About-Turn?" (PDF). Rejuvenation Res 7 (3): 171–4.  
  143. ^ Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006). "High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease". Nat Gen. 38 (5): 515–517.  
  144. ^ Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG (2005). "Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production". PNAS 102 (50): 17993–8.  


See also

A number of changes can occur to mitochondria during the aging process.[140] Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.[141] However, mutated mtDNA can only be found in about 0.2% of very old cells.[142] Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of oxidative stress and neuronal death in Parkinson's disease.[143] However, there is much debate over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in mice demonstrated shortened lifespan but no increase in reactive oxygen species despite increasing mitochondrial DNA mutations.[144] However, it has to be noted that aging non-mutant mice do not seem to accumulate a great number of mutations in mitochondrial DNA imposing a cloud of doubt on the involvement of mitochondrial DNA mutations in "natural" aging. As a result, the exact relationships between mitochondria, oxidative stress, and aging have not yet been settled.

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).[137] Hypothesized links between aging and oxidative stress are not new and were proposed in 1956,[138] which was later refined into the mitochondrial free radical theory of aging.[139] 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.

Possible relationships to aging

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 oxiation. 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.[136]

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.[130] 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.[128] 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.[131][132] Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease,[133] Parkinson's disease, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa, and diabetes mellitus.[134][135]

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.[7] They can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders.[128] Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy.[129] 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's 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.[128]

Mitochondrial diseases

Dysfunction and disease

Recent measurements of the molecular clock for mitochondrial DNA[126] 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[127]).

However, mitochondrial DNA reflects the history of only 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.[123] In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.[125]

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.[120] 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.[121][122] This is often interpreted as strong support for a recent modern human expansion out of Africa.[123] 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 lack of interbreeding between Neanderthals and anatomically modern humans.[124]

Population genetic studies

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.[89] For this reason, mitochondrial DNA usually is 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.[116] Further, evidence suggests that animal mitochondria can undergo recombination.[117] The data are a bit more controversial in humans, although indirect evidence of recombination exists.[118][119] 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.

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 coniferous plants, although not in pine trees and yew trees.[110] For Mytilidae mussels paternal inheritance only occurs within males of the species.[111][112][113] It has been suggested that it occurs at a very low level in humans.[114] There is a recent suggestion mitochondria that shorten male lifespan stay in the system because mitochondria 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 human females and female animals tend to live longer than males. The authors claim this is a partial explanation.[115]

It is worthwhile to point out that the hypothesis of mitochondrial binary fission has relied on the visualization by fluorescence microscopy and conventional transmission electron microscopy (TEM). As is well known, the resolution of fluorescence microscopy(~200 nm) is insufficient to distinguish structural details such as double mitochondrial membrane in mitochondrial division. It is even not sufficient to distinguish individual mitochondrion when multiple mitochondria are close to each other. Conventional TEM has also some technical limitations in verifying mitochondrial division. A cutting edge technique termed Cryo-electron tomography was recently utilized to visualize mitochondrial division in frozen hydrated intact cells. It revealed that mitochondria divide by budding.[107]

Mitochondria divide by binary fission, similar to bacterial cell division.[105] 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.[106]

Replication and inheritance

Mitochondrial genomes have far fewer genes than the Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.[104] 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.[104]

[103] Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of

Exceptions to the standard genetic code in mitochondria[8]
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

While slight variations on the standard code had been predicted earlier,[97] none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code.[98] Although, the mitochondria of many other eukaryotes, including most plants, use the standard code.[99] Many slight variants have been discovered since,[100] including various alternative mitochondrial codes.[101] Further, the AUA, AUC, and AUU codons are all allowable start codons.

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.[96] 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.

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.[24] 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.[90] In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome;[24] however, introns have been observed in some eukaryotic mitochondrial DNA,[91] such as that of yeast[92] and protists,[93] including Dictyostelium discoideum.[94] Between protein-coding regions, tRNAs are present. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleave 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. [95]

The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.[88] 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.[88] One mitochondrion can contain two to ten copies of its DNA.[89]

Mitochondrial DNA.


A few groups of unicellular eukaryotes lack mitochondria: the mitosomes and hydrogenosomes).[1]

The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.[84] 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[85] to 2[86] billion years ago.

The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[83] They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclear DNA.

Phylogeny of Rickettsiales
Other alphaproteobacteria Rhodospirillales, Sphingomonadales, Rhodobacteraceae, Rhizobiales, etc.

SAR11 clade Pelagibacter ubique









Robust phylogeny of Rickettsiales from Williams et al. (2007)[82]

A recent study[81] 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.

A mitochondrion contains 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 twenty-two 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.[79] 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.[80]

There are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotic hypothesis suggests mitochondria were originally prokaryotic cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became endosymbionts living inside the eukaryote. 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 most accredited theory at present is endosymbiosis.[78]


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.[71] The majority of ATP in tumor cells is generated via the Oxidative Phosphorylation pathway (OxPhos).[72] Interference with OxPhos have shown to cause cell cycle arrest suggesting that mitochondria play a role in cell proliferation.[72] 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.[73][74][75] 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.[76] ATP's role in the basic functions of the cell make the cell cycle sensitive to changes in the availability of mitochondrial derived ATP.[76] 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.[76] 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.[77]

Cellular proliferation regulation

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.

  • Regulation of cellular metabolism[66]
  • Certain heme synthesis reactions[67] (see also: porphyrin)
  • Steroid synthesis.[56]
  • Hormonal signaling [68] 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 [69] and heart [70]

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

Additional functions

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.[61] In neurons, concominant 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.[62]

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.[55] In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium.[56][57][58] The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium.[59] The calcium is taken up into the matrix by a calcium uniporter on the inner mitochondrial membrane.[60] It is primarily driven by the mitochondrial membrane potential.[55] 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.[60] 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.

Transmission electron micrograph showing mitochondria (M) within a chondrocyte stained for calcium.

Storage of calcium ions

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.[9] The process is mediated by a proton channel called thermogenin, or UCP1.[53] Thermogenin is a 33kDa protein first discovered in 1973.[54] 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.[53]

Heat production

[52] for their clarification of the working mechanism of ATP synthase.John E. Walker and Paul D. Boyer for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Nobel Prize in Chemistry who was awarded the 1978 [51][50]Peter Mitchell, and was first described by chemiosmosis This process is called [9] As the proton concentration increases in the intermembrane space, a strong

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.[9] 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.[9] This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[49]

Diagram of the electron transport chain in the mitonchondrial intermembrane space

NADH and FADH2: the electron transport chain

The acetyl-CoA is the primary substrate to enter the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle. 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.[48] 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).[9]

Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH.[9]

Pyruvate and the citric acid cycle

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.[9] This process of cellular respiration, also 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.[9] The production of ATP from glucose has an approximately 13-times higher yield during aerobic respiration compared to fermentation.[46] Recently it has been shown that plant mitochondria can produce a limited amount of ATP without oxygen by using the alternate substrate nitrite.[47]

Energy conversion

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.[9] 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.


[45], one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.vimentin Recent evidence suggests that [44] Mitochondria are found in nearly all

Organization and distribution

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.


ERMES tethering complex.
Model of the yeast multimeric tethering complex, ERMES

Recent advances in the identification of the fission and fusion events between individual mitochondria.[25] 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.[25][26] 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.[38][39]

Molecular basis for tethering

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.[37] 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.[25] 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.[25] 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.[36]

But transmission of Ca2+ is not unidirectional; rather, it is a two-way street. 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, clearance of Ca2+ by the MAM allows for spatio-temporal patterning of Ca2+ signaling because Ca2+ alters IP3R activity in a biphasic manner.[25] 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.[34][36] 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.

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.[25][34][35] 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.[25][26][36] 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.[36]

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.[25] 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.[25] Transmission occurs in response to so-called "Ca2+ puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca2+ channel.[25][26]

Calcium signaling

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.[29][33] The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles.[28] 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.[31] Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP.[31] 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.[31][32]


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