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Mitochondrial form and function

Nature volume 505, pages 335343 (16 January 2014) | Download Citation

Abstract

Mitochondria are one of the major ancient endomembrane systems in eukaryotic cells. Owing to their ability to produce ATP through respiration, they became a driving force in evolution. As an essential step in the process of eukaryotic evolution, the size of the mitochondrial chromosome was drastically reduced, and the behaviour of mitochondria within eukaryotic cells radically changed. Recent advances have revealed how the organelle's behaviour has evolved to allow the accurate transmission of its genome and to become responsive to the needs of the cell and its own dysfunction.

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References

  1. 1.

    & The energetics of genome complexity. Nature 467, 929–934 (2010).

  2. 2.

    & Shaping the mitochondrial proteome. Biochim. Biophys. Acta 1659, 212–220 (2004).

  3. 3.

    et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).

  4. 4.

    , , , & A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).

  5. 5.

    et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).

  6. 6.

    et al. The proteome of Saccharomyces cerevisiae mitochondria. Proc. Natl Acad. Sci. USA 100, 13207–13212 (2003).

  7. 7.

    , , , & Quantitative proteomic comparison of rat mitochondria from muscle, heart, and liver. Mol. Cell. Proteomics 5, 608–619 (2006).

  8. 8.

    , & Mitochondrial DNA polymerases from yeast to man: a new family of polymerases. Gene 185, 147–152 (1997).

  9. 9.

    & Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations. Cellular and molecular life sciences. Cell. Mol. Life Sci. 68, 219–233 (2011).

  10. 10.

    et al. Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the expressed sequence tags database. Hum. Mol. Genet. 6, 615–625 (1997).

  11. 11.

    & Mechanism of protein biosynthesis in mammalian mitochondria. Biochim. Biophys. Acta 1819, 1035–1054 (2012).

  12. 12.

    , , & The conserved interaction of C7orf30 with MRPL14 promotes biogenesis of the mitochondrial large ribosomal subunit and mitochondrial translation. Mol. Biol. Cell 24, 184–193 (2013).

  13. 13.

    et al. Structure of the mammalian mitochondrial ribosome reveals an expanded functional role for its component proteins. Cell 115, 97–108 (2003).

  14. 14.

    & Translocation of proteins into mitochondria. Annu. Rev. Biochem. 76, 723–749 (2007).

  15. 15.

    , & Mitochondrial protein import: from proteomics to functional mechanisms. Nature Rev. Mol. Cell Biol. 11, 655–667 (2010).

  16. 16.

    , , & AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

  17. 17.

    , & Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29, 4617–4624 (2010).

  18. 18.

    , & Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459–466 (2012).

  19. 19.

    , , & Localization of mRNAs coding for mitochondrial proteins in the yeast Saccharomyces cerevisiae. RNA 17, 1551–1565 (2011).

  20. 20.

    et al. Mitochondria-associated yeast mRNAs and the biogenesis of molecular complexes. Mol. Biol. Cell 18, 362–368 (2007).

  21. 21.

    et al. Regulation of mitochondrial protein import by cytosolic kinases. Cell 144, 227–239 (2011).

  22. 22.

    & Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).

  23. 23.

    et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988).

  24. 24.

    et al. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann. Neurol. 40, 25–30 (1996).

  25. 25.

    et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013).

  26. 26.

    et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100–109 (2012).

  27. 27.

    , & The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nature Struct. Mol. Biol. 18, 1290–1296 (2011).

  28. 28.

    et al. Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. Nature Struct. Mol. Biol. 18, 1281–1289 (2011).

  29. 29.

    et al. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Mol. Genet. 13, 935–944 (2004).

  30. 30.

    et al. Mammalian transcription factor A is a core component of the mitochondrial transcription machinery. Proc. Natl Acad. Sci. USA 109, 16510–16515 (2012).

  31. 31.

    Mitochondrial DNA nucleoid structure. Biochim. Biophys. Acta 1819, 914–920 (2012).

  32. 32.

    Defects in mitochondrial DNA replication and human disease. Crit. Rev. Biochem. Mol. Biol. 47, 64–74 (2012).

  33. 33.

    , , & Protein components of mitochondrial DNA nucleoids in higher eukaryotes. Mol. Cell. Proteomics 2, 1205–1216 (2003).

  34. 34.

    et al. In organello formaldehyde crosslinking of proteins to mtDNA: identification of bifunctional proteins. Proc. Natl Acad. Sci. USA 97, 7772–7777 (2000).

  35. 35.

    et al. Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis. Nucleic Acids Res. 40, 6109–6121 (2012).

  36. 36.

    et al. Mgm101 is a Rad52-related protein required for mitochondrial DNA recombination. J. Biol. Chem. 286, 42360–42370 (2011).

  37. 37.

    & Human mitochondrial DNA replication. Cold Spring Harb. Perspect. Biol. 4, a012971 (2012).

  38. 38.

    , & Native R-loops persist throughout the mouse mitochondrial DNA genome. J. Biol. Chem. 283, 36743–36751 (2008).

  39. 39.

    et al. Superresolution fluorescence imaging of mitochondrial nucleoids reveals their spatial range, limits, and membrane interaction. Mol. Cell. Biol. 31, 4994–5010 (2011).

  40. 40.

    et al. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc. Natl Acad. Sci. USA 108, 13534–13539 (2011).

  41. 41.

    The inheritance of genes in mitochondria and chloroplasts: laws, mechanisms, and models. Annu. Rev. Genet. 35, 125–148 (2001).

  42. 42.

    et al. Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission. Science 334, 1144–1147 (2011).

  43. 43.

    & Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos. Science 334, 1141–1144 (2011).

  44. 44.

    , , , & Mouse oocytes within germ cell cysts and primordial follicles contain a Balbiani body. Proc. Natl Acad. Sci. USA 104, 187–192 (2007).

  45. 45.

    et al. Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model. Proc. Natl Acad. Sci. USA 110, E3622–E3630 (2013). This paper showed that during reprogramming of heteroplasmic fibroblasts derived from mitochondrial disease patients, mutant and wild-type mitochondrial genomes segregate through a bottleneck towards a homoplasmic state.

  46. 46.

    & Evidence for a two membrane-spanning autonomous mitochondrial DNA replisome. J. Cell Biol. 163, 503–510 (2003).

  47. 47.

    , & The machines that divide and fuse mitochondria. Annu. Rev. Biochem. 76, 751–780 (2007).

  48. 48.

    , & Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130, 548–562 (2007).

  49. 49.

    et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141, 280–289 (2010).

  50. 50.

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

  51. 51.

    et al. Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion. Proc. Natl Acad. Sci. USA 110, E2967–E2976 (2013). This paper demonstrates that mitochondria can undergo hyperfusion and temporarily maintain ATP production to compensate for a reduction of complex IV activity due to loss of the RNA-binding protein LRPPRC.

  52. 52.

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

  53. 53.

    , & Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280, 26185–26192 (2005).

  54. 54.

    et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nature Cell Biol. 11, 958–966 (2009).

  55. 55.

    et al. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3, e3257 (2008).

  56. 56.

    et al. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. 186, 805–816 (2009).

  57. 57.

    et al. Maintenance of mitochondrial morphology is linked to maintenance of the mitochondrial genome in Saccharomyces cerevisiae. Genetics 162, 1147–1156 (2002).

  58. 58.

    et al. Oligomerization of dynamin superfamily proteins in health and disease. Prog. Mol. Biol. Transl. Sci. 117, 411–443 (2013).

  59. 59.

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

  60. 60.

    , , & C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol. Cell 4, 815–826 (1999).

  61. 61.

    , & The crystal structure of dynamin. Nature 477, 561–566 (2011).

  62. 62.

    et al. Structural insights into oligomerization and mitochondrial remodelling of dynamin 1-like protein. EMBO J. 32, 1280–1292 (2013).

  63. 63.

    et al. Crystal structure of nucleotide-free dynamin. Nature 477, 556–560 (2011).

  64. 64.

    , & Mitochondrial fusion intermediates revealed in vitro. Science 305, 1747–1752 (2004).

  65. 65.

    , , & Structure of a bacterial dynamin-like protein lipid tube provides a mechanism for assembly and membrane curving. Cell 139, 1342–1352 (2009).

  66. 66.

    & The division of endosymbiotic organelles. Science 302, 1698–1704 (2003).

  67. 67.

    et al. Dynamic recruitment of dynamin for final mitochondrial severance in a primitive red alga. Proc. Natl Acad. Sci. USA 100, 2146–2151 (2003).

  68. 68.

    et al. ER tubules mark sites of mitochondrial division. Science 334, 358–362 (2011).

  69. 69.

    et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J. Cell Biol. 191, 1141–1158 (2010).

  70. 70.

    , & An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339, 464–467 (2013).

  71. 71.

    et al. An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325, 477–481 (2009).

  72. 72.

    et al. ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. eLife 2, e00422 (2013). In yeast, ERMD serves to segregate mitochondrial genomes into tips of newly divided mitochondria, and the conserved Miro GTPase Gem1 may spatially resolve ER–mitochondrial contacts post-division.

  73. 73.

    , , & Mmm1p, a mitochondrial outer membrane protein, is connected to mitochondrial DNA (mtDNA) nucleoids and required for mtDNA stability. J. Cell Biol. 152, 401–410 (2001).

  74. 74.

    et al. A protein complex containing Mdm10p, Mdm12p, and Mmm1p links mitochondrial membranes and DNA to the cytoskeleton-based segregation machinery. Mol. Biol. Cell 14, 4618–4627 (2003).

  75. 75.

    , , & Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173, 545–557 (2006).

  76. 76.

    , & The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem. Biophys. Res. Commun. 344, 500–510 (2006).

  77. 77.

    , & The functional organization of mitochondrial genomes in human cells. BMC Biol. 2, 9 (2004).

  78. 78.

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

  79. 79.

    , , , & Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome c. Proc. Natl Acad. Sci. USA 110, 11863–11868 (2013).

  80. 80.

    et al. The inner membrane protein Mdm33 controls mitochondrial morphology in yeast. J. Cell Biol. 160, 553–564 (2003).

  81. 81.

    et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nature Genet. 28, 223–231 (2001).

  82. 82.

    , & Making heads or tails of phospholipids in mitochondria. J. Cell Biol. 192, 7–16 (2011).

  83. 83.

    et al. A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. J. Cell Biol. 195, 323–340 (2011).

  84. 84.

    et al. The mitochondrial contact site complex, a determinant of mitochondrial architecture. EMBO J. 30, 4356–4370 (2011).

  85. 85.

    et al. Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis. Dev. Cell 21, 694–707 (2011).

  86. 86.

    , , , & Structure of the yeast F1Fo-ATP synthase dimer and its role in shaping the mitochondrial cristae. Proc. Natl Acad. Sci. USA 109, 13602–13607 (2012).

  87. 87.

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

  88. 88.

    , , & Effects of Fcj1-Mos1 and mitochondrial division on aggregation of mitochondrial DNA nucleoids and organelle morphology. Mol. Biol. Cell 24, 1842–1851 (2013).

  89. 89.

    , , , & ER-shaping proteins facilitate lipid exchange between the ER and mitochondria in S. cerevisiae. J. Cell Sci. 125, 4791–4799 (2012).

  90. 90.

    et al. Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142, 889–901 (2010).

  91. 91.

    et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148, 988–1000 (2012).

  92. 92.

    et al. The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes. Mol. Cell 41, 150–160 (2011).

  93. 93.

    et al. CDIP1–BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress. Cell Rep. 5, 331–339 (2013).

  94. 94.

    & Mitochondria: the next (neurode) generation. Neuron 70, 1033–1053 (2011).

  95. 95.

    et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31, 4106–4123 (2012).

  96. 96.

    et al. Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models. Proc. Natl Acad. Sci. USA 110, 7916–7921 (2013).

  97. 97.

    , , , & Endoplasmic reticulum-associated mitochondria-cortex tether functions in the distribution and inheritance of mitochondria. Proc. Natl Acad. Sci. USA 110, E458–E467 (2013).

  98. 98.

    et al. Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast. Curr. Biol. 21, 1994–1999 (2011).

  99. 99.

    & Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).

  100. 100.

    & Endoplasmic reticulum-mitochondria contacts: function of the junction. Nature Rev. Mol. Cell Biol. 13, 607–625 (2012).

  101. 101.

    et al. Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389–393 (2013).

  102. 102.

    & Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J. Cell Biol. 202, 351–364 (2013). The authors show that the protein syntaphilin can regulate mitochondrial position in neurons by acting as a molecular brake through its binding to the microtubule motor Kif5.

  103. 103.

    , , & Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J. Neurosci. 27, 422–430 (2007).

  104. 104.

    , , , & Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J. Neurosci. 30, 4232–4240 (2010).

  105. 105.

    , & Quality control of mitochondrial proteostasis. Cold Spring Harb. Perspect. Biol. 3, a007559 (2011).

  106. 106.

    et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013).

  107. 107.

    et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002).

  108. 108.

    et al. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur. J. Biochem. 240, 98–103 (1996).

  109. 109.

    , , , & The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol. Cell 37, 529–540 (2010).

  110. 110.

    , , , & Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012). This work demonstrated that in C. elegans, the transcription factor ATFS-1 senses and modulates a response to mitochondrial stress through its targeting to either the mitochondrial matrix or the nucleus.

  111. 111.

    , & Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J. Cell Biol. 178, 757–764 (2007).

  112. 112.

    , , , & Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J. Cell Biol. 187, 959–966 (2009).

  113. 113.

    et al. Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J. Cell Biol. 187, 1023–1036 (2009).

  114. 114.

    , , & Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc. Natl Acad. Sci. USA 108, 10190–10195 (2011).

  115. 115.

    , & During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nature Cell Biol. 13, 589–598 (2011).

  116. 116.

    et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221 (2010).

  117. 117.

    et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).

  118. 118.

    et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147, 893–906 (2011).

  119. 119.

    et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726–1737 (2011).

  120. 120.

    et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).

  121. 121.

    , , , & The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol. Biol. Cell 22, 291–300 (2011).

  122. 122.

    et al. The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc. Natl Acad. Sci. USA 110, 6400–6405 (2013). The authors utilized proteomics of Drosophila Pink1 and Parkin mutants to show that respiratory complex components are selectively turned over compared with other mitochondrial proteins during mitophagy.

  123. 123.

    et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

  124. 124.

    et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

  125. 125.

    , , , & Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc. Natl Acad. Sci. USA 108, 12937–12942 (2011).

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Acknowledgements

We thank members of the Nunnari lab for helpful discussions and comments. We also thank K. Osteryoung and S. Lewis for helpful discussions. J.N. is supported by NIH grants R01GM062942, R01GM097432 and R01GM106019. J.F. is supported by a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research.

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  1. Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, California 95616, USA.

    • Jonathan R. Friedman
    •  & Jodi Nunnari

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The authors declare no competing financial interests.

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Correspondence to Jodi Nunnari.

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