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Mitochondrial dynamics in adaptive and maladaptive cellular stress responses

Mitochondria sense and respond to many stressors and can support cell survival or death through energy production and signalling pathways. Mitochondrial responses depend on fusion–fission dynamics that dilute and segregate damaged mitochondria. Mitochondrial motility and inter-organellar interactions, such as with the endoplasmic reticulum, also function in cellular adaptation to stress. In this Review, we discuss how stressors influence these components, and how they contribute to the complex adaptive and pathological responses that lead to disease.

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Fig. 1: Framework outlining elements of the overall mitochondrial stress response and the link to disease, with a focus on mitochondrial dynamics.
Fig. 2: Components of mitochondrial dynamics and their response to stress.
Fig. 3: Influence of stressor types on mitochondrial stress responses that progress to disease.

References

  1. 1.

    Picard, M., McEwen, B. S., Epel, E. S. & Sandi, C. An energetic view of stress: focus on mitochondria. Front. Neuroendocr. 49, 72–85 (2018).

    CAS  Google Scholar 

  2. 2.

    Youle, R. J. & van der Bliek, A. M. Mitochondrial fission, fusion, and stress. Science 337, 1062–1065 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Suomalainen, A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 2, 77–92 (2017).

    Google Scholar 

  4. 4.

    Liesa, M. & Shirihai, O. S. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 17, 491–506 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lemasters, J. J. Rusty notions of cell injury. J. Hepatol. 40, 696–8 (2004).

    PubMed  Google Scholar 

  6. 6.

    Rizzuto, R., De Stefani, D., Raffaello, A. & Mammucari, C. Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell Biol. 13, 566–78 (2012).

    CAS  PubMed  Google Scholar 

  7. 7.

    Bagur, R. & Hajnoczky, G. Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Mol. Cell 66, 780–788 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Holmstrom, K. M. & Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 15, 411–421 (2014).

    CAS  PubMed  Google Scholar 

  9. 9.

    Nicholls, D., G. Bioenergetics 4th ed. (Academic Press, Cambridge, MA, 2013).

  10. 10.

    Szabo, G. et al. RSA 2004: combined basic research satellite symposium - session three: alcohol and mitochondrial metabolism: at the crossroads of life and death. Alcohol Clin. Exp. Res. 29, 1749–1752 (2005).

    CAS  PubMed  Google Scholar 

  11. 11.

    Montero, J. & Letai, A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 25, 56–64 (2018).

    CAS  PubMed  Google Scholar 

  12. 12.

    Mannella, C. A. Structure and dynamics of the mitochondrial inner membrane cristae. Biochim. Biophys. Acta 1763, 542–548 (2006).

    CAS  PubMed  Google Scholar 

  13. 13.

    Labbé, K., Murley, A. & Nunnari, J. Determinants and functions of mitochondrial behavior. Annu. Rev. Cell Dev. Biol. 30, 357–391 (2014).

  14. 14.

    Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Gong, G. et al. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350, aad2459 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Schwarz, T. L. Mitochondrial trafficking in neurons. Cold Spring Harb. Perspect. Biol. 5, a011304 (2013).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Fransson, A., Ruusala, A. & Aspenstrom, P. Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J. Biol. Chem. 278, 6495–502 (2003).

    CAS  PubMed  Google Scholar 

  18. 18.

    Pathak, D., Sepp, K. J. & Hollenbeck, P. J. Evidence that myosin activity opposes microtubule-based axonal transport of mitochondria. J. Neurosci. 30, 8984–8992 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Quintero, O. A. et al. Human Myo19 is a novel myosin that associates with mitochondria. Curr. Biol. 19, 2008–2013 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Chen, Y. & Sheng, Z. H. Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J. Cell Biol. 202, 351–364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Rohn, J. L. et al. Myo19 ensures symmetric partitioning of mitochondria and coupling of mitochondrial segregation to cell division. Curr. Biol. 24, 2598–2605 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Chung, J. Y., Steen, J. A. & Schwarz, T. L. Phosphorylation-induced motor shedding is required at mitosis for proper distribution and passive inheritance of mitochondria. Cell Rep. 16, 2142–2155 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Nguyen, T. T. et al. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc. Natl. Acad. Sci. USA 111, 3631–3640 (2014).

    Google Scholar 

  24. 24.

    Vaccaro, V., Devine, M. J., Higgs, N. F. & Kittler, J. T. Miro1-dependent mitochondrial positioning drives the rescaling of presynaptic Ca2+ signals during homeostatic plasticity. EMBO Rep. 18, 231–240 (2017).

    CAS  PubMed  Google Scholar 

  25. 25.

    Yi, M., Weaver, D. & Hajnoczky, G. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J. Cell Biol. 167, 661–672 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Liu, X., Weaver, D., Shirihai, O. & Hajnóczky, G. Mitochondrial ‘kiss-and-run’: interplay between mitochondrial motility and fusion-fission dynamics. EMBO J. 28, 3074–3089 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Sheng, Z. H. Mitochondrial trafficking and anchoring in neurons: New insight and implications. J. Cell Biol. 204, 1087–1098 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Lopez-Domenech, G. et al. Loss of dendritic complexity precedes neurodegeneration in a mouse model with disrupted mitochondrial distribution in mature dendrites. Cell Rep. 17, 317–327 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lopez-Domenech, G. et al. Miro proteins coordinate microtubule- and actin-dependent mitochondrial transport and distribution. EMBO J. 37, 321–336 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Misko, A., Jiang, S., Wegorzewska, I., Milbrandt, J. & Baloh, R. H. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J. Neurosci. 30, 4232–4240 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Baloh, R. H. Mitochondrial dynamics and peripheral neuropathy. Neuroscientist 14, 12–18 (2008).

    CAS  PubMed  Google Scholar 

  32. 32.

    Saotome, M. et al. Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc. Natl. Acad. Sci. USA 105, 20728–20733 (2008).

    CAS  PubMed  Google Scholar 

  33. 33.

    Stephen, T. L. et al. Miro1 regulates activity-driven positioning of mitochondria within astrocytic processes apposed to synapses to regulate intracellular calcium signaling. J. Neurosci. 35, 15996–16011 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Fang, C., Bourdette, D. & Banker, G. Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases. Mol. Neurodegener. 7, 29 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Debattisti, V., Gerencser, A. A., Saotome, M., Das, S. & Hajnoczky, G. ROS control mitochondrial motility through p38 and the motor adaptor Miro/Trak. Cell Rep. 21, 1667–1680 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Pekkurnaz, G., Trinidad, J. C., Wang, X., Kong, D. & Schwarz, T. L. Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase. Cell 158, 54–68 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Liao, P. C., Tandarich, L. C. & Hollenbeck, P. J. ROS regulation of axonal mitochondrial transport is mediated by Ca2+ and JNK in Drosophila. PLoS ONE 12, e0178105 (2017).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Iqbal, S. & Hood, D. A. Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts. Am. J. Physiol. Cell Physiol. 306, 1176–1183 (2014).

    Google Scholar 

  39. 39.

    Li, L. et al. p38 MAP kinase-dependent phosphorylation of the Gp78 E3 ubiquitin ligase controls ER-mitochondria association and mitochondria motility. Mol. Biol. Cell 26, 3828–3840 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Han, S. M., Baig, H. S. & Hammarlund, M. Mitochondria localize to injured axons to support regeneration. Neuron 92, 1308–1323 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Zhou, B. et al. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J. Cell Biol. 214, 103–119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Lin, M. Y. et al. Releasing syntaphilin removes stressed mitochondria from axons independent of mitophagy under pathophysiological conditions. Neuron 94, 595–610 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Caino, M. C. et al. Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J. Clin. Invest. 127, 3755–3769 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Birsa, N. et al. Lysine 27 ubiquitination of the mitochondrial transport protein Miro is dependent on serine 65 of the Parkin ubiquitin ligase. J. Biol. Chem. 289, 14569–14582 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    O’Mealey, G. B. et al. A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. J. Cell Sci. 130, 3467–3480 (2017).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Al-Mehdi, A. B. et al. Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci. Signal 5, ra47 (2012).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Usaj, M. & Henn, A. Kinetic adaptation of human Myo19 for active mitochondrial transport to growing filopodia tips. Sci. Rep. 7, 11596 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Cartoni, R. et al. The mammalian-specific protein Armcx1 regulates mitochondrial transport during axon regeneration. Neuron 92, 1294–1307 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Song, Z., Ghochani, M., McCaffery, J. M., Frey, T. G. & Chan, D. C. Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol. Biol. Cell 20, 3525–3532 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Weaver, D. et al. Distribution and apoptotic function of outer membrane proteins depend on mitochondrial fusion. Mol. Cell 54, 870–878 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Otera, H. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Osellame, L. D. et al. Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission. J. Cell Sci. 129, 2170–2181 (2016).

    CAS  PubMed  Google Scholar 

  54. 54.

    Ji, W. K., Hatch, A. L., Merrill, R. A., Strack, S. & Higgs, H. N. Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. eLife 4, e11553 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Lee, J. E., Westrate, L. M., Wu, H., Page, C. & Voeltz, G. K. Multiple dynamin family members collaborate to drive mitochondrial division. Nature 540, 139–143 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Ono, T., Isobe, K., Nakada, K. & Hayashi, J. I. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat. Genet. 28, 272–275 (2001).

    CAS  PubMed  Google Scholar 

  57. 57.

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

    CAS  PubMed  Google Scholar 

  58. 58.

    Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–46 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Eisner, V., Lenaers, G. & Hajnoczky, G. Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. J. Cell Biol. 205, 179–195 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Lewis, S. C., Uchiyama, L. F. & Nunnari, J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353, aaf5549 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Boldogh, I. R. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    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).

    CAS  PubMed  Google Scholar 

  64. 64.

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

    CAS  PubMed  Google Scholar 

  65. 65.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

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

    CAS  PubMed  Google Scholar 

  67. 67.

    Cartoni, R. et al. Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A. Brain 133, 1460–1469 (2010).

    PubMed  Google Scholar 

  68. 68.

    Strickland, A. V. et al. Characterization of the mitofusin 2 R94W mutation in a knock-in mouse model. J. Peripher. Nerv. Syst. 19, 152–164 (2014).

    CAS  PubMed  Google Scholar 

  69. 69.

    Alavi, M. V. et al. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain 130, 1029–1042 (2007).

    PubMed  Google Scholar 

  70. 70.

    Chen, Y. et al. Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. Circ. Res. 111, 863–875 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Chen, Y., Liu, Y. & Dorn, G. W. 2nd Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ. Res. 109, 1327–1331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Papanicolaou, K. N. et al. Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ. Res. 111, 1012–26 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W. & Scorrano, L. Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling. Science 342, 734–737 (2013).

    CAS  PubMed  Google Scholar 

  74. 74.

    Hall, A. R. et al. Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell Death Dis. 7, e2238 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Tezze, C. et al. Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab. 25, 1374–1389 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Rodríguez-Nuevo, A. et al. Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. EMBO J. 37, e96553 (2018).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Detmer, S. A., Vande Velde, C., Cleveland, D. W. & Chan, D. C. Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Hum. Mol. Genet. 17, 367–375 (2008).

    CAS  PubMed  Google Scholar 

  79. 79.

    Bannerman, P., Burns, T., Xu, J., Miers, L. & Pleasure, D. Mice hemizygous for a pathogenic mitofusin-2 allele exhibit hind limb/foot gait deficits and phenotypic perturbations in nerve and muscle. PLoS ONE 11, e0167573 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Williams, P. A., Morgan, J. E. & Votruba, M. Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy. Brain 133, 2942–2951 (2010).

    PubMed  Google Scholar 

  81. 81.

    Kushnareva, Y. et al. Mitochondrial dysfunction in an Opa1(Q285STOP) mouse model of dominant optic atrophy results from Opa1 haploinsufficiency. Cell Death Dis. 7, e2309 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Chen, L. et al. OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. J. Am. Heart Assoc. 1, e003012 (2012).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Sarzi, E. et al. The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse. Brain 135, 3599–3613 (2012).

    PubMed  Google Scholar 

  84. 84.

    Soriano, F. X. et al. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 55, 1783–1791 (2006).

    CAS  PubMed  Google Scholar 

  85. 85.

    Chen, Y. & Dorn, G. W. 2nd PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471–475 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Shutt, T., Geoffrion, M., Milne, R. & McBride, H. M. The intracellular redox state is a core determinant of mitochondrial fusion. EMBO Rep. 13, 909–915 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Samant, S. A. et al. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol. Cell Biol. 34, 807–819 (2014).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Park, Y. Y. et al. Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1. J. Cell Sci. 123, 619–626 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Head, B., Griparic, L., Amiri, M., Gandre-Babbe, S. & van der Bliek, A. M. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J. Cell Biol. 187, 959–966 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Mishra, P., Carelli, V., Manfredi, G. & Chan, D. C. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 19, 630–641 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Ban, T. et al. Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nat. Cell Biol. 19, 856–863 (2017).

    CAS  PubMed  Google Scholar 

  93. 93.

    Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589–598 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Rainbolt, T. K., Lebeau, J., Puchades, C. & Wiseman, R. L. Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteolytic activity during stress. Cell Rep. 14, 2041–2049 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Tondera, D. et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 28, 1589–1600 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Wai, T. et al. The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L. EMBO Rep. 17, 1844–1856 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Zemirli, N. et al. Mitochondrial hyperfusion promotes NF-κB activation via the mitochondrial E3 ligase MULAN. FEBS J. 281, 3095–3112 (2014).

    CAS  PubMed  Google Scholar 

  98. 98.

    Nan, J. et al. TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression. Circ. Res. 121, 392–410 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Rambold, A. S., Kostelecky, B. & Lippincott-Schwartz, J. Together we are stronger: fusion protects mitochondria from autophagosomal degradation. Autophagy 7, 1568–1569 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Molina, A. J. et al. Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes 58, 2303–2315 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Yu, T., Sheu, S. S., Robotham, J. L. & Yoon, Y. Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc. Res. 79, 341–351 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Wu, S., Zhou, F., Zhang, Z. & Xing, D. Mitochondrial oxidative stress causes mitochondrial fragmentation via differential modulation of mitochondrial fission-fusion proteins. FEBS J. 278, 941–954 (2011).

    CAS  PubMed  Google Scholar 

  103. 103.

    Toyama, E. Q. et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Sabouny, R. et al. The Keap1-Nrf2 stress response pathway promotes mitochondrial hyperfusion through degradation of the mitochondrial fission protein Drp1. Antioxid. Redox Signal 27, 1447–1459 (2017).

    CAS  PubMed  Google Scholar 

  105. 105.

    Cereghetti, G. M. et al. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc. Natl. Acad. Sci. USA 105, 15803–15808 (2008).

    CAS  PubMed  Google Scholar 

  106. 106.

    Picard, M. et al. Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm. J. Appl. Physiol. 118, 1161–1171 (2015).

    CAS  PubMed  Google Scholar 

  107. 107.

    Pfluger, P. T. et al. Calcineurin links mitochondrial elongation with energy metabolism. Cell Metab. 22, 838–850 (2015).

    CAS  PubMed  Google Scholar 

  108. 108.

    Helle, S. C. J. et al. Mechanical force induces mitochondrial fission. eLife 6, e30292 (2017).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Campello, S. et al. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J. Exp. Med. 203, 2879–2886 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Liu, X. & Hajnoczky, G. Altered fusion dynamics underlie unique morphological changes in mitochondria during hypoxia-reoxygenation stress. Cell Death Differ. 18, 1561–1572 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Vincent, A. E., Turnbull, D. M., Eisner, V., Hajnoczky, G. & Picard, M. Mitochondrial nanotunnels. Trends Cell Biol. 27, 787–799 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Huang, X. et al. Kissing and nanotunneling mediate intermitochondrial communication in the heart. Proc. Natl. Acad. Sci. USA 110, 2846–2851 (2013).

    CAS  PubMed  Google Scholar 

  114. 114.

    Wang, C. et al. Dynamic tubulation of mitochondria drives mitochondrial network formation. Cell Res. 25, 1108–1120 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Eisner, V. et al. Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. Proc. Natl. Acad. Sci. USA 114, 859–868 (2017).

    Google Scholar 

  116. 116.

    Lavorato, M. et al. Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges. Proc. Natl. Acad. Sci. USA 114, 849–858 (2017).

    Google Scholar 

  117. 117.

    Vincent, A. E. et al. The spectrum of mitochondrial ultrastructural defects in mitochondrial myopathy. Sci. Rep. 6, 30610 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Picard, M. et al. Trans-mitochondrial coordination of cristae at regulated membrane junctions. Nat. Commun. 6, 6259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Picard, M. et al. Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle. J. Appl. Physiol. 115, 1562–1571 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Vernay, A. et al. MitoNEET-dependent formation of intermitochondrial junctions. Proc. Natl. Acad. Sci. USA 114, 8277–8282 (2017).

    CAS  PubMed  Google Scholar 

  121. 121.

    Prinz, W. A. Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics. J. Cell Biol. 205, 759–769 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Csordas, G., Weaver, D. & Hajnoczky, G. Endoplasmic reticular-mitochondrial contactology: structure and signaling functions. Trends Cell Biol. http://doi.org/cqgf (2018).

  123. 123.

    Yang, Z., Zhao, X., Xu, J., Shang, W. & Tong, C. A novel fluorescent reporter detects plastic remodeling of mitochondria-ER contact sites. J. Cell Sci. 131, jcs20868 (2017).

    Google Scholar 

  124. 124.

    Csordas, G. et al. Structural and functional features and significance of the physical linkage between ER and mitochondria. J. Cell Biol. 174, 915–921 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Cieri, D. et al. SPLICS: a split green fluorescent protein-based contact site sensor for narrow and wide heterotypic organelle juxtaposition. Cell Death Differ. http://doi.org/cqgg (2017).

  126. 126.

    Sutendra, G. et al. The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci. Transl. Med. 3, 88ra55 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Qiao, X. et al. PTPIP51 regulates mouse cardiac ischemia/reperfusion through mediating the mitochondria-SR junction. Sci. Rep. 7, 45379 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Zhang, A. et al. Quantitative proteomic analyses of human cytomegalovirus-induced restructuring of endoplasmic reticulum-mitochondrial contacts at late times of infection. Mol. Cell Proteom. 10, M111 009936 (2011).

    Google Scholar 

  129. 129.

    Horner, S. M., Wilkins, C., Badil, S., Iskarpatyoti, J. & Gale, M. Jr. Proteomic analysis of mitochondrial-associated ER membranes (MAM) during RNA virus infection reveals dynamic changes in protein and organelle trafficking. PLoS ONE 10, e0117963 (2015).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Lynes, E. M. et al. Palmitoylation is the switch that assigns calnexin to quality control or ER Ca2+ signaling. J. Cell Sci. 126, 3893–3903 (2013).

    CAS  PubMed  Google Scholar 

  131. 131.

    Gilady, S. Y. et al. Ero1alpha requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM). Cell Stress Chaperon-. 15, 619–629 (2010).

    CAS  Google Scholar 

  132. 132.

    Joseph, S. K. Role of thiols in the structure and function of inositol trisphosphate receptors. Curr. Top. Membr. 66, 299–322 (2010).

    CAS  PubMed  Google Scholar 

  133. 133.

    Hidalgo, C., Aracena, P., Sanchez, G. & Donoso, P. Redox regulation of calcium release in skeletal and cardiac muscle. Biol. Res. 35, 183–193 (2002).

    CAS  PubMed  Google Scholar 

  134. 134.

    SanMartín, C. D. et al. RyR2-mediated Ca2+ release and mitochondrial ROS generation partake in the synaptic dysfunction caused by amyloid β peptide oligomers. Front. Mol. Neurosci. 10, 115 (2017).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Khan, M. T. & Joseph, S. K. Role of inositol trisphosphate receptors in autophagy in DT40 cells. J. Biol. Chem. 285, 16912–16920 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Hacki, J. et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19, 2286–2295 (2000).

    CAS  PubMed  Google Scholar 

  137. 137.

    Nutt, L. K. et al. Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores. J. Biol. Chem. 277, 9219–9225 (2002).

    CAS  PubMed  Google Scholar 

  138. 138.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32, 678–692 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Lapuente-Brun, E. et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science 340, 1567–1570 (2013).

    CAS  PubMed  Google Scholar 

  141. 141.

    Hackenbrock, C. R. Ultrastructural bases for metabolically linked mechanical activity in mitochondria: I reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. J. Cell Biol. 30, 269–297 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Strauss, M., Hofhaus, G., Schröder, R. R. & Kühlbrandt, W. Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J. 27, 1154–1160 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Friedman, J. R., Mourier, A., Yamada, J., McCaffery, J. M. & Nunnari, J. MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture. eLife 4, e07739 (2015).

    PubMed Central  Google Scholar 

  144. 144.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Tarasenko, D. et al. The MICOS component Mic60 displays a conserved membrane-bending activity that is necessary for normal cristae morphology. J. Cell Biol. 216, 889–899 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

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

    CAS  PubMed  Google Scholar 

  147. 147.

    Nielsen, J. et al. Plasticity in mitochondrial cristae density allows metabolic capacity modulation in human skeletal muscle. J. Physiol. 595, 2839–2847 (2017).

    CAS  PubMed  Google Scholar 

  148. 148.

    Patten, D. A. et al. OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 33, 2676–2691 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Yamaguchi, R. et al. Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol. Cell 31, 557–569 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Norton, M. et al. ROMO1 is an essential redox-dependent regulator of mitochondrial dynamics. Sci. Signal 7, ra10 (2014).

    PubMed  Google Scholar 

  151. 151.

    Rossignol, R. et al. Mitochondrial threshold effects. Biochem. J. 370, 751–762 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Zuchner, S. et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 36, 449–451 (2004).

    PubMed  Google Scholar 

  153. 153.

    Gerber, S. et al. Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission. Brain 140, 2586–2596 (2017).

    PubMed  Google Scholar 

  154. 154.

    Koch, J. et al. Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy. J. Med. Genet. 53, 270–278 (2016).

    CAS  PubMed  Google Scholar 

  155. 155.

    Barel, O. et al. Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain 140, 568–581 (2017).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Alexander, C. et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat. Genet. 26, 211–215 (2000).

    CAS  PubMed  Google Scholar 

  157. 157.

    Delettre, C. et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat. Genet. 26, 207–210 (2000).

    CAS  PubMed  Google Scholar 

  158. 158.

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

    PubMed  Google Scholar 

  159. 159.

    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).

    PubMed  Google Scholar 

  160. 160.

    Schrepfer, E. & Scorrano, L. Mitofusins, from Mitochondria to Metabolism. Mol. Cell 61, 683–694 (2016).

    CAS  PubMed  Google Scholar 

  161. 161.

    Wikstrom, J. D. et al. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J. 33, 418–436 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Yu, T., Robotham, J. L. & Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. USA 103, 2653–2658 (2006).

    CAS  PubMed  Google Scholar 

  163. 163.

    Schneeberger, M. et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172–187 (2013).

    CAS  PubMed  Google Scholar 

  164. 164.

    Ramirez, S. et al. Mitochondrial dynamics mediated by Mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control. Cell Metab. 25, 1390–1399 (2017).

    CAS  PubMed  Google Scholar 

  165. 165.

    Kumar, R. et al. Mitochondrial dynamics following global cerebral ischemia. Mol. Cell Neurosci. 76, 68–75 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Tian, L. et al. Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. J. Mol. Med. 95, 381–393 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Meyer, J. N. et al. Mitochondria as a target of environmental toxicants. Toxicol. Sci. 134, 1–17 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Picard, M. & Turnbull, D. M. Linking the metabolic state and mitochondrial DNA in chronic disease, health, and aging. Diabetes 62, 672–678 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Arruda, A. P. et al. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427–1435 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Kirkman, M. A. et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain 132, 2317–2326 (2009).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Schon, E. A. & Przedborski, S. Mitochondria: the next (neurode)generation. Neuron 70, 1033–1053 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Smith, E. F., Shaw, P. J. & De Vos, K. J. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci. Lett. http://doi.org/cqgh (2017).

  173. 173.

    Guardia-Laguarta, C., Area-Gomez, E., Schon, E. A. & Przedborski, S. A new role for alpha-synuclein in Parkinson’s disease: Alteration of ER-mitochondrial communication. Mov. Disord. 30, 1026–1033 (2015).

    CAS  PubMed  Google Scholar 

  174. 174.

    Area-Gomez, E. & Schon, E. A. On the Pathogenesis of Alzheimer’s Disease: The MAM Hypothesis. FASEB J. 31, 864–867 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Hedskog, L. 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).

    CAS  PubMed  Google Scholar 

  176. 176.

    Lewis, T. L. Jr., Turi, G. F., Kwon, S. K., Losonczy, A. & Polleux, F. Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo. Curr. Biol. 26, 2602–2608 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Song, M., Franco, A., Fleischer, J. A., Zhang, L. & Dorn, G. W. Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab. 26, 872–883 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Le Page, S. et al. Increase in cardiac ischemia-reperfusion injuries in Opa1± mouse model. PLoS ONE 11, e0164066 (2016).

    PubMed  PubMed Central  Google Scholar 

  179. 179.

    Renata, O. P. et al. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J. 36, 2126–2145 (2017).

    Google Scholar 

  180. 180.

    Zhang, Z. et al. The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol. Biol. Cell 22, 2235–2245 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank David Weaver and Orian Shirihai for comments. This work was supported by FONDECYT 1150677 to VE, the Wharton Fund, NIH-R35-GM119793 and R21-MH113011 to MP, and R01-DK51526, R33-ES025672 and UO1-AA021122 to GH.

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Eisner, V., Picard, M. & Hajnóczky, G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol 20, 755–765 (2018). https://doi.org/10.1038/s41556-018-0133-0

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