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Mitochondrial fragmentation in neurodegeneration

Nature Reviews Neuroscience volume 9, pages 505–518 (2008)Cite this article

Key Points

  • Mitochondria are dynamic organelles that undergo continuous cycles of fission and fusion. These dynamic processes allow mitochondria to communicate, migrate and adapt to changing energy demands and cellular conditions.

  • A group of large GTPases mediate mitochondrial fission and fusion. Important players in mammalian cells include mitofusin 1 and 2 (MFN1 and MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1).

  • Mutations in the mitochondrial fission and fusion GTPases MFN2, OPA1 and DRP1 cause neurodegenerative diseases. MFN2 mutations cause Charcot-Marie-Tooth subtype 2A (CMT2A) and sensory neuropathy type VI (HMSN VI), OPA1 mutations cause autosomal dominant optic atrophy (ADOA), and a DRP1 mutation caused a lethal defect in a human infant.

  • Several triggers, including oxidative stress and altered regulation by cell-cycle kinases, contribute to the cell-specific shift in the balance between fission and fusion that is characteristic of sporadic neurodegenerative diseases.

  • The emerging roles of mitochondrial fission and fusion, including synaptic maintenance, bioenergetics and genetic drift of mitochondrial DNA subpopulations, along with an increased appreciation of differences in the mitochondrial proteome in different cell types, might help to explain some of the unique characteristics of sporadic neurodegenerative diseases, such as their late onset and slow progression.

  • Transcriptional regulation of mitochondrial biogenesis, exercise and reactive oxygen species management are three potential ways of reversing deleterious changes in mitochondrial dynamics.

Abstract

Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in the mitochondrial fusion GTPases mitofusin 2 and optic atrophy 1, neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired bioenergetics and mitochondrial migration, and can trigger neurodegeneration. These findings suggest potential new treatment avenues for neurodegenerative diseases.

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Figure 1: Neuronal mitochondria.
Figure 2: Mitochondrial fusion.
Figure 3: Mitochondrial fission.
Figure 4: Mutations in MFN2 and OPA1 in human patients.
Figure 5: Gene shift and exercise.

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References

  1. Chan, D. C. Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241–1252 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Hoppins, S., Lackner, L. & Nunnari, J. The machines that divide and fuse mitochondria. Annu. Rev. Biochem. 76, 751–780 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, Y. & Chan, D. C. New insights into mitochondrial fusion. FEBS Lett. 581, 2168–2173 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baloh, R. H., Schmidt, R. E., Pestronk, A. & Milbrandt, J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J. Neurosci. 27, 422–430 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen, H., McCaffery, J. M. & Chan, D. C. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130, 548–562 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Chen, H. et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 160, 189–200 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barsoum, M. J. et al. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J. 25, 3900–3911 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bereiter-Hahn, J. & Voth, M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc. Res. Tech. 27, 198–219 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Nunnari, J. et al. Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA. Mol. Biol. Cell 8, 1233–1242 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Urrutia, R., Henley, J. R., Cook, T. & McNiven, M. A. The dynamins: redundant or distinct functions for an expanding family of related GTPases? Proc. Natl Acad. Sci. USA 94, 377–384 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hermann, G. J. et al. Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J. Cell Biol. 143, 359–373 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sesaki, H. & Jensen, R. E. Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J. Cell Biol. 147, 699–706 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wong, E. D. et al. The intramitochondrial dynamin-related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion. J. Cell Biol. 160, 303–311 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Griffin, E. E. & Chan, D. C. Domain interactions within Fzo1 oligomers are essential for mitochondrial fusion. J. Biol. Chem. 281, 16599–16606 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Meeusen, S., McCaffery, J. M. & Nunnari, J. Mitochondrial fusion intermediates revealed in vitro. Science 305, 1747–1752 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Ishihara, N., Eura, Y. & Mihara, K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J. Cell Sci. 117, 6535–6546 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Koshiba, T. et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science 305, 858–862 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Low, H. H. & Lowe, J. A bacterial dynamin-like protein. Nature 444, 766–769 (2006). This study provided the first structure of a full-length dynamin-like protein.

    Article  CAS  PubMed  Google Scholar 

  20. Chen, H., Chomyn, A. & Chan, D. C. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280, 26185–26192 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Cipolat, S., Martins de Brito, O., Dal Zilio, B. & Scorrano, L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl Acad. Sci. USA 101, 15927–15932 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Davies, V. J. et al. Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum. Mol. Genet. 16, 1307–1318 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Olichon, A. et al. The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett. 523, 171–176 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Yarosh, W. et al. The molecular mechanisms of OPA1-mediated optic atrophy in Drosophila model and prospects for antioxidant treatment. PLoS Genet. 4, e6 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Meeusen, S. et al. Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127, 383–395 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Griparic, L., Kanazawa, T. & van der Bliek, A. M. Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J. Cell Biol. 178, 757–764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Song, Z., Chen, H., Fiket, M., Alexander, C. & Chan, D. C. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J. Cell Biol. 178, 749–755 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duvezin-Caubet, S. et al. OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria. Mol. Biol. Cell 18, 3582–3590 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Labrousse, A. M., Zappaterra, M. D., Rube, D. A. & van der Bliek, A. M. C . elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol. Cell 4, 815–826 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Legesse-Miller, A., Massol, R. H. & Kirchhausen, T. Constriction and Dnm1p recruitment are distinct processes in mitochondrial fission. Mol. Biol. Cell 14, 1953–1963 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Naylor, K. et al. Mdv1 interacts with assembled Dnm1 to promote mitochondrial division. J. Biol. Chem. 281, 2177–2183 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Smirnova, E., Griparic, L., Shurland, D. L. & van der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cerveny, K. L. & Jensen, R. E. The WD-repeats of Net2p interact with Dnm1p and Fis1p to regulate division of mitochondria. Mol. Biol. Cell 14, 4126–4139 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Karren, M. A., Coonrod, E. M., Anderson, T. K. & Shaw, J. M. The role of Fis1p-Mdv1p interactions in mitochondrial fission complex assembly. J. Cell Biol. 171, 291–301 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang, Y. & Chan, D. C. Structural basis for recruitment of mitochondrial fission complexes by Fis1. Proc. Natl Acad. Sci. USA 104, 18526–18530 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yoon, Y., Krueger, E. W., Oswald, B. J. & McNiven, M. A. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol. Cell. Biol. 23, 5409–5420 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L. & Youle, R. J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell 15, 5001–5011 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wasiak, S., Zunino, R. & McBride, H. M. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J. Cell Biol. 177, 439–450 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ingerman, E. et al. Dnm1 forms spirals that are structurally tailored to fit mitochondria. J. Cell Biol. 170, 1021–1027 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Niemann, A., Ruegg, M., La Padula, V., Schenone, A. & Suter, U. Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J. Cell Biol. 170, 1067–1078 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Detmer, S. A. & Chan, D. C. Functions and dysfunctions of mitochondrial dynamics. Nature Rev. Mol. Cell Biol. 8, 870–879 (2007).

    Article  CAS  Google Scholar 

  44. Chang, C. R. & Blackstone, C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J. Biol. Chem. 282, 21583–21587 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Cribbs, J. T. & Strack, S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 8, 939–944 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Taguchi, N., Ishihara, N., Jofuku, A., Oka, T. & Mihara, K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 282, 11521–11529 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Meuer, K. et al. Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. Cell Death Differ. 14, 651–661 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Harder, Z., Zunino, R. & McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Karbowski, M., Neutzner, A. & Youle, R. J. The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J. Cell Biol. 178, 71–84 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nakamura, N., Kimura, Y., Tokuda, M., Honda, S. & Hirose, S. MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep. 7, 1019–1022 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yonashiro, R. et al. A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO J. 25, 3618–3626 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Karbowski, M. et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J. Cell Biol. 159, 931–938 (2002). References 52 and 53 were two of the first studies to describe the relationship between mitochondrial fission and cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jagasia, R., Grote, P., Westermann, B. & Conradt, B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433, 754–760 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Abdelwahid, E. et al. Mitochondrial disruption in Drosophila apoptosis. Dev. Cell 12, 793–806 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Goyal, G., Fell, B., Sarin, A., Youle, R. J. & Sriram, V. Role of mitochondrial remodeling in programmed cell death in Drosophila melanogaster. Dev. Cell 12, 807–816 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Scheckhuber, C. Q. et al. Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nature Cell Biol. 9, 99–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Leinninger, G. M. et al. Mitochondria in DRG neurons undergo hyperglycaemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol. Dis. 23, 11–22 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Yuan, H. et al. Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death Differ. 14, 462–471 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Brooks, C. et al. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc. Natl Acad. Sci. USA 104, 11649–11654 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Karbowski, M., Norris, K. L., Cleland, M. M., Jeong, S. Y. & Youle, R. J. Role of Bax and Bak in mitochondrial morphogenesis. Nature 443, 658–662 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Estaquier, J. & Arnoult, D. Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis. Cell Death Differ. 14, 1086–1094 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. James, D. I., Parone, P. A., Mattenberger, Y. & Martinou, J. C. hFis1, a novel component of the mammalian mitochondrial fission machinery. J. Biol. Chem. 278, 36373–36379 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Parone, P. A. et al. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol. Cell. Biol. 26, 7397–7408 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Alirol, E. et al. The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis. Mol. Biol. Cell 17, 4593–4605 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bras, M. et al. Drp1 mediates caspase-independent type III cell death in normal and leukemic cells. Mol. Cell. Biol. 27, 7073–7088 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bredesen, D. E., Rao, R. V. & Mehlen, P. Cell death in the nervous system. Nature 443, 796–802 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873–887 (2004). This paper underscored the importance of mitochondrial fission and fusion in synaptic development.

    Article  CAS  PubMed  Google Scholar 

  69. Benard, G. et al. Mitochondrial bioenergetics and structural network organization. J. Cell Sci. 120, 838–848 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Santel, A. Get the balance right: mitofusins roles in health and disease. Biochim. Biophys. Acta 1763, 490–499 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Kijima, K. et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum. Genet. 116, 23–27 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Zuchner, S. et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genet. 36, 449–451 (2004). References 71 and 72 were the first to show that mutations in MFN2 cause CMT2A.

    Article  PubMed  CAS  Google Scholar 

  73. Zuchner, S. et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann. Neurol. 59, 276–281 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Carelli, V., Ross-Cisneros, F. N. & Sadun, A. A. Mitochondrial dysfunction as a cause of optic neuropathies. Prog. Retin. Eye Res. 23, 53–89 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Amati-Bonneau, P. et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes. Brain 131, 338–351 (2008).

    Article  PubMed  Google Scholar 

  76. Hudson, G. et al. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain 131, 329–337 (2008). References 75 and 76 describe new optic atrophy 'plus' phenotypes caused by mutations in OPA1.

    Article  PubMed  Google Scholar 

  77. Detmer, S. A. & Chan, D. C. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J. Cell Biol. 176, 405–414 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chan, D. C. Mitochondrial fusion and fission in mammals. Annu. Rev. Cell Dev. Biol. 22, 79–99 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Griffin, E. E., Detmer, S. A. & Chan, D. C. Molecular mechanism of mitochondrial membrane fusion. Biochim. Biophys. Acta 1763, 482–489 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Waterham, H. R. et al. A lethal defect of mitochondrial and peroxisomal fission. N. Engl. J. Med. 356, 1736–1741 (2007). This was the first report of a DRP1 mutation in a human patient.

    Article  CAS  PubMed  Google Scholar 

  81. Baxter, R. V. et al. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nature Genet. 30, 21–22 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Cuesta, A. et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nature Genet. 30, 22–25 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Kabzinska, D. et al. Early onset Charcot-Marie-Tooth disease caused by a homozygous Leu239Phe mutation in the GDAP1 gene. Acta Myol. 25, 34–37 (2006).

    CAS  PubMed  Google Scholar 

  84. Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Jahani-Asl, A. et al. Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death. J. Biol. Chem. 282, 23788–23798 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Smith, P. D., O'Hare, M. J. & Park, D. S. CDKs: taking on a role as mediators of dopaminergic loss in Parkinson's disease. Trends Mol. Med. 10, 445–451 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Park, D. S., Levine, B., Ferrari, G. & Greene, L. A. Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J. Neurosci. 17, 8975–8983 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Park, D. S. et al. Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents. J. Cell Biol. 143, 457–467 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nguyen, M. D. et al. Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J. Neurosci. 23, 2131–2140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Osuga, H. et al. Cyclin-dependent kinases as a therapeutic target for stroke. Proc. Natl Acad. Sci. USA 97, 10254–10259 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Busser, J., Geldmacher, D. S. & Herrup, K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J. Neurosci. 18, 2801–2807 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Smith, P. D. et al. Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 26, 440–447 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Johansson, A. et al. Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 20, 367–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Johnson, D. T., Harris, R. A., Blair, P. V. & Balaban, R. S. Functional consequences of mitochondrial proteome heterogeneity. Am. J. Physiol. Cell Physiol. 292, C698–C707 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Chang, D. T. & Reynolds, I. J. Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture. Neuroscience 141, 727–736 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Jonas, E. BCL-xL regulates synaptic plasticity. Mol. Interv. 6, 208–222 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Reddy, P. H. & Beal, M. F. Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res. Brain Res. Rev. 49, 618–632 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Rikhy, R., Kamat, S., Ramagiri, S., Sriram, V. & Krishnan, K. S. Mutations in dynamin-related protein result in gross changes in mitochondrial morphology and affect synaptic vesicle recycling at the Drosophila neuromuscular junction. Genes Brain Behav. 6, 42–53 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Li, H. et al. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc. Natl Acad. Sci. USA 105, 2169–2174 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Verstreken, P. et al. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47, 365–378 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).

    Article  CAS  PubMed  Google Scholar 

  102. Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wallace, D. C. Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu. Rev. Biochem. 76, 781–821 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Cao, Z., Wanagat, J., McKiernan, S. H. & Aiken, J. M. Mitochondrial DNA deletion mutations are concomitant with ragged red regions of individual, aged muscle fibers: analysis by laser-capture microdissection. Nucleic Acids Res. 29, 4502–4508 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gokey, N. G. et al. Molecular analyses of mtDNA deletion mutations in microdissected skeletal muscle fibers from aged rhesus monkeys. Aging Cell 3, 319–326 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Kowald, A., Jendrach, M., Pohl, S., Bereiter-Hahn, J. & Hammerstein, P. On the relevance of mitochondrial fusions for the accumulation of mitochondrial deletion mutants: a modelling study. Aging Cell 4, 273–283 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Diaz, F. et al. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res. 30, 4626–4633 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Moraes, C. T., Kenyon, L. & Hao, H. Mechanisms of human mitochondrial DNA maintenance: the determining role of primary sequence and length over function. Mol. Biol. Cell 10, 3345–3356 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Elson, J. L., Samuels, D. C., Turnbull, D. M. & Chinnery, P. F. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 68, 802–806 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bogenhagen, D. F., Rousseau, D. & Burke, S. The layered structure of human mitochondrial DNA nucleoids. J. Biol. Chem. 283, 3665–3675 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Garrido, N. et al. Composition and dynamics of human mitochondrial nucleoids. Mol. Biol. Cell 14, 1583–1596 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jacobs, H. T., Lehtinen, S. K. & Spelbrink, J. N. No sex please, we're mitochondria: a hypothesis on the somatic unit of inheritance of mammalian mtDNA. Bioessays 22, 564–572 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Johnson, D. T. et al. Tissue heterogeneity of the mammalian mitochondrial proteome. Am. J. Physiol. Cell Physiol. 292, C689–C697 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Kelly, D. P. & Scarpulla, R. C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357–368 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. St-Pierre, J. et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional co-activators. Cell 127, 397–408 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Cui, L. et al. Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127, 59–69 (2006). References 117 and 118 describe a potential role for PGC1α and mitochondrial biogenesis in neurodegenerative disease.

    Article  CAS  PubMed  Google Scholar 

  119. Handschin, C. et al. PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev. 21, 770–783 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. van Praag, H., Christie, B. R., Sejnowski, T. J. & Gage, F. H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl Acad. Sci. USA 96, 13427–13431 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. McCloskey, D. P., Adamo, D. S. & Anderson, B. J. Exercise increases metabolic capacity in the motor cortex and striatum, but not in the hippocampus. Brain Res. 891, 168–175 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Irrcher, I., Adhihetty, P. J., Joseph, A. M., Ljubicic, V. & Hood, D. A. Regulation of mitochondrial biogenesis in muscle by endurance exercise. Sports Med. 33, 783–793 (2003).

    Article  PubMed  Google Scholar 

  124. Pilegaard, H., Saltin, B. & Neufer, P. D. Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. J. Physiol. 546, 851–858 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Short, K. R. et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl Acad. Sci. USA 102, 5618–5623 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Krishnan, K. J., Greaves, L. C., Reeve, A. K. & Turnbull, D. M. Mitochondrial DNA mutations and aging. Ann. NY Acad. Sci. 1100, 227–240 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Melov, S., Tarnopolsky, M. A., Beckman, K., Felkey, K. & Hubbard, A. Resistance exercise reverses aging in human skeletal muscle. PLoS ONE 2, e465 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Cartoni, R. et al. Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise. J. Physiol. 567, 349–358 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Bach, D. et al. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J. Biol. Chem. 278, 17190–17197 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Taivassalo, T. et al. Gene shifting: a novel therapy for mitochondrial myopathy. Hum. Mol. Genet. 8, 1047–1052 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Parise, G., Brose, A. N. & Tarnopolsky, M. A. Resistance exercise training decreases oxidative damage to DNA and increases cytochrome oxidase activity in older adults. Exp. Gerontol. 40, 173–180 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. DiMauro, S., Hirano, M. & Schon, E. A. Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34, 265–283 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Taivassalo, T. & Haller, R. G. Exercise and training in mitochondrial myopathies. Med. Sci. Sports Exerc. 37, 2094–2101 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Kukidome, D. et al. Activation of AMP-activated protein kinase reduces hyperglycaemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55, 120–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. St-Pierre, J. et al. Bioenergetic analysis of peroxisome proliferator-activated receptor γ co-activators 1α and 1β (PGC-1α and PGC-1β) in muscle cells. J. Biol. Chem. 278, 26597–26603 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. Lehman, J. J. et al. Peroxisome proliferator-activated receptor γ co-activator-1 promotes cardiac mitochondrial biogenesis. J. Clin. Invest. 106, 847–856 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nunomura, A. et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Crouch, P. J. et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1–42 . J. Neurosci. 25, 672–679 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Manczak, M. et al. Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15, 1437–1449 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci. 3, 1301–1306 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Fornai, F. et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and α-synuclein. Proc. Natl Acad. Sci. USA 102, 3413–3418 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Damiano, M. et al. Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J. Neurochem. 96, 1349–1361 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Liu, J. et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43, 5–17 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Mattiazzi, M. et al. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277, 29626–29633 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Pasinelli, P. et al. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43, 19–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Milakovic, T. & Johnson, G. V. Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J. Biol. Chem. 280, 30773–30782 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. Benchoua, A. et al. Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol. Biol. Cell 17, 1652–1663 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Panov, A. V. et al. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nature Neurosci. 5, 731–736 (2002).

    Article  CAS  PubMed  Google Scholar 

  149. Poole, A. C. et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc. Natl Acad. Sci. USA 105, 1638–1643 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Yang, Y. et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc. Natl Acad. Sci. USA 105, 7070–7075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We apologize to all colleagues whose articles we were unable to cite owing to space limitations. We wish to acknowledge the support of US National Institutes of Health grants RO1 EY016164 (E.B.W.), RO1 NS047456 (E.B.W.), RO1 NS055193 (E.B.W.), P41 RR004050 (G.P.) and P42 ES010337 (G.P.), as well as European Union grants MCEXT-033534 and MCIRG-046536 (R.S.). We thank A. Wilson for help with illustrations.

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Authors and Affiliations

  1. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida Boulevard, Orlando, 32816, Florida, USA

    Andrew B. Knott & Ella Bossy-Wetzel

  2. National Center for Microscopy and Imaging Research, School of Medicine, University of California, San Diego, La Jolla, 92093, California, USA

    Guy Perkins

  3. Department of Molecular Biology, University of Salzburg, Salzburg, 5020, Austria

    Robert Schwarzenbacher

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  1. Andrew B. Knott
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Correspondence to Ella Bossy-Wetzel.

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DATABASES

OMIM

ADOA

ALS

Alzheimer's disease

CMT2A

CMT4A

HMSN VI

Huntington's disease

Parkinson's disease

FURTHER INFORMATION

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Glossary

Mitochondrial fission

The separation of a long, tubular mitochondrion (2–25 μm in length) into two or more smaller parts (∼0.5 μm in diameter).

Mitochondrial fusion

The combination of two mitochondria into a single organelle. It occurs at the tips or on the sides of the mitochondria.

Synapses

Specialized junctions through which neurons communicate with each other and with other cell types (for example, muscle cells) through the exchange of chemical messengers.

Oxidative phosphorylation

The reaction pathway that converts nutrients into ATP by transferring electrons from donors to acceptors, such as molecular oxygen. The enzymes that mediate this process reside in or associate closely with the mitochondrial inner membrane.

GTPases

A large family of enzymes that bind and hydrolyse high-energy GTP into low-energy GDP and phosphate; the released energy is used to drive changes in protein conformation.

Cristae

Mitochondrial inner membrane portions that protrude into the mitochondrial matrix.

They contain electron transport chain enzymes and ATP synthase.

Phosphorylation

The addition of a phosphate group to a protein by a kinase. Phosphorylation is a common post-translational modification that modulates protein activity.

Sumoylation

The addition of a small ubiquitin-related modifier (SUMO) to a protein. Sumoylation is a post-translational modification that generally stabilizes and extends the lifespan of a protein.

Ubiquitylation

The addition of the small protein ubiquitin to another protein. Ubiquitylation marks proteins for degradation by the proteasome.

Staurosporine

A non-selective protein kinase inhibitor that induces apoptosis.

Etoposide

An inhibitor of topoisomerase II that induces apoptosis and is an anti-cancer drug.

Oxidative stress

A condition in which increased amounts of reactive oxygen species, free radicals and peroxides damage lipids, proteins and DNA.

Reactive oxygen species

(ROS). These include oxygen anions, free radicals and peroxides, which form as byproducts of oxygen metabolism. Mitochondria are a major source of ROS.

Purkinje cells

Large, GABA (g-aminobutyric acid)-ergic neurons that are found in the cerebellar cortex and that have a role in motor coordination.

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Knott, A., Perkins, G., Schwarzenbacher, R. et al. Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9, 505–518 (2008). https://doi.org/10.1038/nrn2417

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