Review Article | Published:

Mitochondrial dynamics in adaptive and maladaptive cellular stress responses

Nature Cell Biologyvolume 20pages755765 (2018) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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).

  2. 2.

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

  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).

  4. 4.

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

  5. 5.

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

  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).

  7. 7.

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

  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).

  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).

  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).

  12. 12.

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

  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).

  15. 15.

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

  16. 16.

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

  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).

  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).

  19. 19.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  27. 27.

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

  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).

  29. 29.

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

  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).

  31. 31.

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

  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).

  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).

  34. 34.

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

  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).

  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).

  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).

  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).

  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).

  40. 40.

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

  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).

  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).

  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).

  44. 44.

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

  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).

  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).

  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).

  48. 48.

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

  49. 49.

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

  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).

  51. 51.

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

  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).

  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).

  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).

  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).

  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).

  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).

  58. 58.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  66. 66.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  77. 77.

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

  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).

  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).

  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).

  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).

  82. 82.

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

  83. 83.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  95. 95.

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

  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).

  97. 97.

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

  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).

  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).

  100. 100.

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

  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).

  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).

  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).

  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).

  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).

  106. 106.

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

  107. 107.

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

  108. 108.

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

  109. 109.

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

  110. 110.

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

  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).

  112. 112.

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

  113. 113.

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

  114. 114.

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

  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).

  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).

  117. 117.

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

  118. 118.

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

  119. 119.

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

  120. 120.

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

  121. 121.

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

  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).

  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).

  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).

  127. 127.

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

  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).

  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).

  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).

  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).

  132. 132.

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

  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).

  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).

  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).

  136. 136.

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

  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).

  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).

  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).

  140. 140.

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

  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).

  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).

  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).

  144. 144.

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

  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).

  146. 146.

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

  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).

  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).

  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).

  150. 150.

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

  151. 151.

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

  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).

  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).

  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).

  155. 155.

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

  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).

  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).

  158. 158.

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

  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).

  160. 160.

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

  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).

  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).

  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).

  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).

  165. 165.

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

  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).

  167. 167.

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

  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).

  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).

  170. 170.

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

  171. 171.

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

  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).

  174. 174.

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

  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).

  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).

  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).

  178. 178.

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

  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).

  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).

Download references

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.

Author information

Affiliations

  1. Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    • Verónica Eisner
  2. Division of Behavioral Medicine, Departments of Psychiatry and Neurology, The Merritt Center, Columbia Translational Neuroscience Initiative, Columbia Aging Center, Columbia University Medical Center, New York, NY, USA

    • Martin Picard
  3. MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

    • György Hajnóczky

Authors

  1. Search for Verónica Eisner in:

  2. Search for Martin Picard in:

  3. Search for György Hajnóczky in:

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to György Hajnóczky.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41556-018-0133-0