1932

Abstract

The concept that mitochondria are highly dynamic is as widely accepted as it is untrue for a number of important contexts. Healthy mitochondria of the most energy-dependent and mitochondrial-rich mammalian organ, the heart, only rarely undergo fusion or fission and are seemingly static within cardiac myocytes. Here, we revisit mitochondrial dynamism with a fresh perspective developed from the recently discovered multifunctionality of mitochondrial fusion proteins and newly defined mechanisms for direct cross talk between mitochondrial dynamics, biogenesis, quality control, and trafficking pathways. Insights gained from comparing static mitochondrial biology in cardiac myocytes and dynamic mitochondrial biology in neurons are reviewed with the goal of understanding contextual fallacies of overly generalized characterizations of these essential and intriguing organelles.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-020518-114358
2019-02-10
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/physiol/81/1/annurev-physiol-020518-114358.html?itemId=/content/journals/10.1146/annurev-physiol-020518-114358&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Dorn GW 2nd. 2015. Mitochondrial dynamism and heart disease: changing shape and shaping change. EMBO Mol. Med. 7:865–77
    [Google Scholar]
  2. 2.  Chen Y, Liu Y, Dorn GW 2nd. 2011. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ. Res. 109:1327–31
    [Google Scholar]
  3. 3.  Song M, Dorn GW 2nd. 2015. Mitoconfusion: noncanonical functioning of dynamism factors in static mitochondria of the heart. Cell Metab 21:195–205
    [Google Scholar]
  4. 4.  Eisner V, Cupo RR, Gao E, Csordas G, Slovinsky WS et al. 2017. Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. PNAS 114:E859–68
    [Google Scholar]
  5. 5.  Shirihai OS, Song M, Dorn GW 2nd. 2015. How mitochondrial dynamism orchestrates mitophagy. Circ. Res. 116:1835–49
    [Google Scholar]
  6. 6.  Dorn GW 2nd, Kitsis RN 2015. The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ. Res. 116:167–82
    [Google Scholar]
  7. 7.  Kraus F, Ryan MT 2017. The constriction and scission machineries involved in mitochondrial fission. J. Cell Sci. 130:2953–60
    [Google Scholar]
  8. 8.  Ramachandran R. 2018. Mitochondrial dynamics: the dynamin superfamily and execution by collusion. Semin. Cell Dev. Biol. 76:201–12
    [Google Scholar]
  9. 9.  Chan DC. 2012. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46:265–87
    [Google Scholar]
  10. 10.  Ishihara N, Eura Y, Mihara K 2004. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J. Cell Sci. 117:6535–46
    [Google Scholar]
  11. 11.  Pernas L, Scorrano L 2016. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu. Rev. Physiol. 78:505–31
    [Google Scholar]
  12. 12.  Chen Y, Dorn GW 2nd. 2013. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–75
    [Google Scholar]
  13. 13.  Gong G, Song M, Csordas G, Kelly DP, Matkovich SJ, Dorn GW 2nd. 2015. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350:aad2459
    [Google Scholar]
  14. 14.  Baloh RH, Schmidt RE, Pestronk A, Milbrandt J 2007. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J. Neurosci. 27:422–30
    [Google Scholar]
  15. 15.  Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH 2010. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J. Neurosci. 30:4232–40
    [Google Scholar]
  16. 16.  Detmer SA, Chan DC 2007. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J. Cell Biol. 176:405–14
    [Google Scholar]
  17. 17.  Schwarz TL. 2013. Mitochondrial trafficking in neurons. Cold Spring Harb. Perspect. Biol. 5:a011304
    [Google Scholar]
  18. 18.  Barlan K, Gelfand VI 2017. Microtubule-based transport and the distribution, tethering, and organization of organelles. Cold Spring Harb. Perspect. Biol. 9:a025817
    [Google Scholar]
  19. 19.  Rocha AG, Franco A, Krezel AM, Runsey JM, Alberti JM et al. 2018. MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science 360:336–41
    [Google Scholar]
  20. 20.  Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM et al. 2004. Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–62
    [Google Scholar]
  21. 21.  Franco A, Kitsis RN, Fleischer JA, Gavathiotis E, Kornfeld OS et al. 2016. Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature 540:74–79
    [Google Scholar]
  22. 22.  Qi Y, Yan L, Yu C, Guo X, Zhou X et al. 2016. Structures of human mitofusin 1 provide insight into mitochondrial tethering. J. Cell Biol. 215:621–29
    [Google Scholar]
  23. 23.  Cao YL, Meng S, Chen Y, Feng JX, Gu DD et al. 2017. MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature 542:372–76
    [Google Scholar]
  24. 24.  Mattie S, Riemer J, Wideman JG, McBride HM 2018. A new mitofusin topology places the redox-regulated C terminus in the mitochondrial intermembrane space. J. Cell Biol. 217:507–15
    [Google Scholar]
  25. 25.  Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E 2008. Mitochondrial fragmentation in neurodegeneration. Nat. Rev. Neurosci. 9:505–18
    [Google Scholar]
  26. 26.  Low HH, Löwe J 2006. A bacterial dynamin-like protein. Nature 444:766–69
    [Google Scholar]
  27. 27.  Low HH, Sachse C, Amos LA, Lowe J 2009. Structure of a bacterial dynamin-like protein lipid tube provides a mechanism for assembly and membrane curving. Cell 139:1342–52
    [Google Scholar]
  28. 28.  Ford MG, Jenni S, Nunnari J 2011. The crystal structure of dynamin. Nature 477:561–66
    [Google Scholar]
  29. 29.  Reubold TF, Faelber K, Plattner N, Posor Y, Ketel K et al. 2015. Crystal structure of the dynamin tetramer. Nature 525:404–8
    [Google Scholar]
  30. 30.  Gao S, von der Malsburg A, Paeschke S, Behlke J, Haller O et al. 2010. Structural basis of oligomerization in the stalk region of dynamin-like MxA. Nature 465:502–6
    [Google Scholar]
  31. 31.  Chen Y, Csordas G, Jowdy C, Schneider TG, Csordas N et al. 2012. Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. Circ. Res. 111:863–75
    [Google Scholar]
  32. 32.  Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I et al. 2011. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol. Cell. Biol. 31:1309–28
    [Google Scholar]
  33. 33.  de Brito OM, Scorrano L 2008. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–10
    [Google Scholar]
  34. 34.  Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F et al. 2016. Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. PNAS 113:11249–54
    [Google Scholar]
  35. 35.  Lee S, Sterky FH, Mourier A, Terzioglu M, Cullheim S et al. 2012. Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons. Hum. Mol. Genet. 21:4827–35
    [Google Scholar]
  36. 36.  Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL et al. 2010. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. PNAS 107:378–83
    [Google Scholar]
  37. 37.  Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA et al. 2010. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLOS Biol 8:e1000298
    [Google Scholar]
  38. 38.  Dorn GW 2nd. 2013. Mitochondrial dynamism and cardiac fate–a personal perspective. Circ. J. 77:1370–79
    [Google Scholar]
  39. 39.  Narendra D, Tanaka A, Suen DF, Youle RJ 2008. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183:795–803
    [Google Scholar]
  40. 40.  Pallanck L. 2013. Mitophagy: mitofusin recruits a mitochondrial killer. Curr. Biol. 23:R570–72
    [Google Scholar]
  41. 41.  Wadman M. 2008. The winding road from ideas to income. Nature 453:830–31
    [Google Scholar]
  42. 42.  Bhandari P, Song M, Chen Y, Burelle Y, Dorn GW 2nd. 2014. Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin. Circ. Res. 114:257–65
    [Google Scholar]
  43. 43.  Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF et al. 2010. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191:1367–80
    [Google Scholar]
  44. 44.  Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH et al. 2010. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19:4861–70
    [Google Scholar]
  45. 45.  Lee Y, Dawson VL, Dawson TM 2012. Animal models of Parkinson's disease: vertebrate genetics. Cold Spring Harb. Perspect. Med. 2:a009324
    [Google Scholar]
  46. 46.  Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP et al. 2015. Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 87:371–81
    [Google Scholar]
  47. 47.  Scarffe LA, Stevens DA, Dawson VL, Dawson TM 2014. Parkin and PINK1: much more than mitophagy. Trends Neurosci 37:315–24
    [Google Scholar]
  48. 48.  Kubli DA, Zhang X, Lee Y, Hanna RA, Quinsay MN et al. 2013. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J. Biol. Chem. 288:915–26
    [Google Scholar]
  49. 49.  Song M, Gong G, Burelle Y, Gustafsson AB, Kitsis RN et al. 2015. Interdependence of Parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. Circ. Res. 117:346–51
    [Google Scholar]
  50. 50.  Dorn GW 2nd. 2016. Parkin-dependent mitophagy in the heart. J. Mol. Cell. Cardiol. 95:42–49
    [Google Scholar]
  51. 51.  Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD et al. 2008. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–46
    [Google Scholar]
  52. 52.  Dorn GW 2nd, Vega RB, Kelly DP 2015. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev 29:1981–91
    [Google Scholar]
  53. 53.  Chen H, McCaffery JM, Chan DC 2007. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–62
    [Google Scholar]
  54. 54.  Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO et al. 2009. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 11:958–66
    [Google Scholar]
  55. 55.  Sohal DS, Nghiem M, Crackower MA, Witt SA, Kimball TR et al. 2001. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ. Res. 89:20–25
    [Google Scholar]
  56. 56.  Song M, Mihara K, Chen Y, Scorrano L, Dorn GW 2nd. 2015. Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–85
    [Google Scholar]
  57. 57.  Song M, Franco A, Fleischer JA, Zhang L, Dorn GW 2nd. 2017. Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab 26:872–83.e5
    [Google Scholar]
  58. 58.  Diwan A, Dorn GW 2nd. 2007. Decompensation of cardiac hypertrophy: cellular mechanisms and novel therapeutic targets. Physiology 22:56–64
    [Google Scholar]
  59. 59.  Dorn GW 2nd. 2007. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 49:962–70
    [Google Scholar]
  60. 60.  Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C et al. 2008. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev. Cell 14:193–204
    [Google Scholar]
  61. 61.  Qi X, Qvit N, Su YC, Mochly-Rosen D 2013. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J. Cell Sci. 126:789–802
    [Google Scholar]
  62. 62.  Joshi AU, Saw NL, Vogel H, Cunnigham AD, Shamloo M et al. 2018. Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol. Med. 2018:e8166
    [Google Scholar]
  63. 63.  Mallat A, Uchiyama LF, Lewis SC, Fredenburg RA, Terada Y et al. 2018. Discovery and characterization of selective small molecule inhibitors of the mammalian mitochondrial division dynamin, DRP1. Biochem. Biophys. Res. Commun. 499:556–62
    [Google Scholar]
  64. 64.  Huang X, Zhou X, Hu X, Joshi AS, Guo X et al. 2017. Sequences flanking the transmembrane segments facilitate mitochondrial localization and membrane fusion by mitofusin. PNAS 114:e9863–72
    [Google Scholar]
  65. 65.  Giacomello M, Scorrano L 2018. The INs and OUTs of mitofusins. J. Cell Biol. 217:439–40
    [Google Scholar]
  66. 66.  Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S et al. 2014. Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. JAMA Neurol 71:1036–42
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-020518-114358
Loading
/content/journals/10.1146/annurev-physiol-020518-114358
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error