Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mechanisms of mitophagy in cellular homeostasis, physiology and pathology

Abstract

Mitophagy is an evolutionarily conserved cellular process to remove dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial number and preserving energy metabolism. In this Review, we survey recent advances towards elucidating the molecular mechanisms that mediate mitochondrial elimination and the signalling pathways that govern mitophagy. We consider the contributions of mitophagy in physiological and pathological contexts and discuss emerging findings, highlighting the potential value of mitophagy modulation in therapeutic intervention.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Mechanisms of mitochondrial selective autophagy.
Fig. 2: Physiological roles of mitophagy.
Fig. 3: Chemical modulators of energy metabolism.
Fig. 4: Milestones in mitophagy research.

References

  1. 1.

    Palikaras, K., Daskalaki, I., Markaki, M. & Tavernarakis, N. Mitophagy and age-related pathologies: Development of new therapeutics by targeting mitochondrial turnover. Pharmacol. Ther. 178, 157–174 (2017).

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Ashrafi, G. & Schwarz, T. L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 (2013).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Khaminets, A., Behl, C. & Dikic, I. Ubiquitin-dependent And independent signals in selective autophagy. Trends Cell Biol. 26, 6–16 (2016).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Pickles, S., Vigie, P. & Youle, R. J. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28, R170–R185 (2018).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Harper, J. W., Ordureau, A. & Heo, J. M. Building and decoding ubiquitin chains for mitophagy. Nat. Rev. Mol. Cell Biol. 19, 93–108 (2018).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Sekine, S. & Youle, R. J. PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol. 16, 2 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Hasson, S. A. et al. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504, 291–295 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Aguirre, J. D., Dunkerley, K. M., Mercier, P. & Shaw, G. S. Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation. Proc. Natl Acad. Sci. USA 114, 298–303 (2017).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Ordureau, A. et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol. Cell 56, 360–375 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Bingol, B. et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 (2014).

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Cornelissen, T. et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum. Mol. Genet. 23, 5227–5242 (2014).

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Cunningham, C. N. et al. USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Nat. Cell Biol. 17, 160–169 (2015).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Gersch, M. et al. Mechanism and regulation of the Lys6-selective deubiquitinase USP30. Nat. Struct. Mol. Biol. 24, 920–930 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Wang, Y. et al. Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy 11, 595–606 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Ordureau, A. et al. Dynamics of PARKIN-dependent mitochondrial ubiquitylation in induced neurons and model systems revealed by digital snapshot proteomics. Mol. Cell 70, 211–227 (2018).

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Rose, C. M. et al. Highly multiplexed quantitative mass spectrometry analysis of ubiquitylomes. Cell Syst. 3, 395–403 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Sarraf, S. A. et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496, 372–376 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    McLelland, G. L., Lee, S. A., McBride, H. M. & Fon, E. A. Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system. J. Cell Biol. 214, 275–291 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Pryde, K. R., Smith, H. L., Chau, K. Y. & Schapira, A. H. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J. Cell Biol. 213, 163–171 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Soubannier, V. et al. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22, 135–141 (2012).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Burman, J. L. et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J. Cell Biol. 216, 3231–3247 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    McLelland, G. L. et al. Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. eLife 7, e32866 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Gelmetti, V. et al. PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation. Autophagy 13, 654–669 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Shlevkov, E., Kramer, T., Schapansky, J., LaVoie, M. J. & Schwarz, T. L. Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. Proc. Natl Acad. Sci. USA 113, 6097–6106 (2016).

    Article  CAS  Google Scholar 

  29. 29.

    Fu, M. et al. Regulation of mitophagy by the Gp78 E3 ubiquitin ligase. Mol. Biol. Cell 24, 1153–1162 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Lokireddy, S. et al. The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab. 16, 613–624 (2012).

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Orvedahl, A. et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480, 113–117 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Szargel, R. et al. The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Hum Mol. Genet. 25, 3476–3490 (2016).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Villa, E. et al. Parkin-independent mitophagy controls chemotherapeutic response in cancer cells. Cell Rep. 20, 2846–2859 (2017).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Heo, J. M., Ordureau, A., Paulo, J. A., Rinehart, J. & Harper, J. W. The PINK1–PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60, 7–20 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Moore, A. S. & Holzbaur, E. L. Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc. Natl Acad. Sci. USA 113, E3349–3358 (2016).

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Richter, B. et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc. Natl Acad. Sci. USA 113, 4039–4044 (2016).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Ding, W. X. et al. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J. Biol. Chem. 285, 27879–27890 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).

    PubMed  Article  CAS  Google Scholar 

  40. 40.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Zhang, J. et al. ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat. Cell Biol. 17, 1259–1269 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Zhong, Z. et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242 (2018).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Kanki, T. et al. Casein kinase 2 is essential for mitophagy. EMBO Rep. 14, 788–794 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Mao, K., Wang, K., Liu, X. & Klionsky, D. J. The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Dev. Cell 26, 9–18 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Murakawa, T. et al. Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat. Commun. 6, 7527 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Bhujabal, Z. et al. FKBP8 recruits LC3A to mediate Parkin-independent mitophagy. EMBO Rep. 18, 947–961 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Lim, G. G. & Lim, K. L. Parkin-independent mitophagy-FKBP8 takes the stage. EMBO Rep. 18, 864–865 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Diwan, A. et al. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J. Clin. Invest. 117, 2825–2833 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Esteban-Martinez, L. et al. Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J. 36, 1688–1706 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Sandoval, H. et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232–235 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Schweers, R. L. et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl Acad. Sci. USA 104, 19500–19505 (2007).

    PubMed  Article  Google Scholar 

  53. 53.

    Schwarten, M. et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy 5, 690–698 (2009).

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Rogov, V. V. et al. Phosphorylation of the mitochondrial autophagy receptor Nix enhances its interaction with LC3 proteins. Sci. Rep. 7, 1131 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Melser, S. et al. Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab. 17, 719–730 (2013).

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Quinsay, M. N., Thomas, R. L., Lee, Y. & Gustafsson, A. B. Bnip3-mediated mitochondrial autophagy is independent of the mitochondrial permeability transition pore. Autophagy 6, 855–862 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Quinsay, M. N. et al. Bnip3 mediates permeabilization of mitochondria and release of cytochrome c via a novel mechanism. J. Mol. Cell Cardiol. 48, 1146–1156 (2010).

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Zhang, T. et al. BNIP3 protein suppresses PINK1 kinase proteolytic cleavage to promote mitophagy. J. Biol. Chem. 291, 21616–21629 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. 59.

    Lee, Y., Lee, H. Y., Hanna, R. A. & Gustafsson, A. B. Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 301, 1924–1931 (2011).

    Article  CAS  Google Scholar 

  60. 60.

    Gao, F. et al. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum. Mol. Genet. 24, 2528–2538 (2015).

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015).

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Liu, L. et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol. 14, 177–185 (2012).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Chen, G. et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol. Cell 54, 362–377 (2014).

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Chen, M. et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy 12, 689–702 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Wu, W. et al. FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions. EMBO J. 35, 1368–1384 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Wu, W. et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 15, 566–575 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67.

    Palikaras, K., Lionaki, E. & Tavernarakis, N. Mitophagy: In sickness and in health. Mol. Cell Oncol. 3, e1056332 (2016).

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Schiavi, A. et al. Iron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C. elegans. Curr. Biol. 25, 1810–1822 (2015).

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Wei, Y., Chiang, W. C., Sumpter, R. Jr., Mishra, P. & Levine, B. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168, 224–238 (2017).

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Xiao, Y., Zhou, Y., Lu, Y., Zhou, K. & Cai, W. PHB2 interacts with LC3 and SQSTM1 is required for bile acids-induced mitophagy in cholestatic liver. Cell Death Dis. 9, 160 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Chu, C. T. et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat. Cell Biol. 15, 1197–1205 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Shen, Z., Li, Y., Gasparski, A. N., Abeliovich, H. & Greenberg, M. L. Cardiolipin regulates mitophagy through the protein kinase C pathway. J. Biol. Chem. 292, 2916–2923 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    McWilliams, T. G. et al. Mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J. Cell Biol. 214, 333–345 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Sun, N. et al. Measuring in vivo mitophagy. Mol. Cell 60, 685–696 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    McWilliams, T. G. et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 27, 439–449 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Le Guerroue, F. et al. Autophagosomal content profiling reveals an LC3C-dependent piecemeal mitophagy pathway. Mol. Cell 68, 786–796 (2017).

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Lee, J. J. et al. Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin. J. Cell Biol. http://doi.org/gdjh3h (2018).

  78. 78.

    Glick, D. et al. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol. Cell Biol. 32, 2570–2584 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79.

    Yasuda, M., Han, J. W., Dionne, C. A., Boyd, J. M. & Chinnadurai, G. BNIP3α: a human homolog of mitochondrial proapoptotic protein BNIP3. Cancer Res. 59, 533–537 (1999).

    PubMed  CAS  Google Scholar 

  80. 80.

    Whitworth, A. J. & Pallanck, L. J. PINK1/Parkin mitophagy and neurodegeneration-what do we really know in vivo? Curr. Opin. Genet. Dev. 44, 47–53 (2017).

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Kanki, T., Wang, K., Cao, Y., Baba, M. & Klionsky, D. J. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev. Cell 17, 98–109 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Kanki, T. & Klionsky, D. J. Mitophagy in yeast occurs through a selective mechanism. J. Biol. Chem. 283, 32386–32393 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Okamoto, K., Kondo-Okamoto, N. & Ohsumi, Y. A landmark protein essential for mitophagy: Atg32 recruits the autophagic machinery to mitochondria. Autophagy 5, 1203–1205 (2009).

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Eiyama, A., Kondo-Okamoto, N. & Okamoto, K. Mitochondrial degradation during starvation is selective and temporally distinct from bulk autophagy in yeast. FEBS Lett. 587, 1787–1792 (2013).

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Zhang, H. et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283, 10892–10903 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Wu, H. & Chen, Q. Hypoxia activation of mitophagy and its role in disease pathogenesis. Antioxid. Redox Signal 22, 1032–1046 (2015).

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Maugeri, G. et al. Parkin modulates expression of HIF-1α and HIF-3α during hypoxia in gliobastoma-derived cell lines in vitro. Cell Tissue Res. 364, 465–474 (2016).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Hirota, Y. et al. Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways. Autophagy 11, 332–343 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Yamano, K., Fogel, A. I., Wang, C., van der Bliek, A. M. & Youle, R. J. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90.

    Puri, C. et al. The RAB11A-positive compartment is a primary platform for autophagosome assembly mediated by WIPI2 recognition of PI3P-RAB11A. Dev. Cell 45, 114–131 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Jimenez-Orgaz, A. et al. Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy. EMBO J. 37, 235–254 (2018).

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Yamano, K. et al. Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 7, e31326 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Honda, S. et al. Ulk1-mediated Atg5-independent macroautophagy mediates elimination of mitochondria from embryonic reticulocytes. Nat. Commun. 5, 4004 (2014).

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Novak, I. et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11, 45–51 (2010).

    PubMed  Article  CAS  Google Scholar 

  95. 95.

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

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Rojansky, R., Cha, M. Y. & Chan, D. C. Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife 5, e17896 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

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

    PubMed  Article  CAS  Google Scholar 

  98. 98.

    Gottlieb, R. A. & Bernstein, D. METABOLISM. Mitochondria shape cardiac metabolism. Science 350, 1162–1163 (2015).

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Vazquez-Martin, A. et al. Mitophagy-driven mitochondrial rejuvenation regulates stem cell fate. Aging 8, 1330–1352 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100.

    Xiang, G. et al. BNIP3L-dependent mitophagy accounts for mitochondrial clearance during 3 factors-induced somatic cell reprogramming. Autophagy 13, 1543–1555 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

    Hu, C. et al. Energy metabolism plays a critical role in stem cell maintenance and differentiation. Int. J. Mol. Sci. 17, 253 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Folmes, C. D. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 14, 264–271 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Billia, F. et al. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc. Natl Acad. Sci. USA 108, 9572–9577 (2011).

    PubMed  Article  Google Scholar 

  104. 104.

    Hoshino, A. et al. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4, 2308 (2013).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Zhang, W., Siraj, S., Zhang, R. & Chen, Q. Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury. Autophagy 13, 1080–1081 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. 106.

    Zhang, W. et al. Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury. eLife 5, e21407 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Manczak, M., Kandimalla, R., Yin, X. & Reddy, P. H. Hippocampal mutant APP and amyloid β-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease. Hum. Mol. Genet. 27, 1332–1342 (2018).

    PubMed  Article  Google Scholar 

  108. 108.

    Sorrentino, V. et al. Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature 552, 187–193 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  109. 109.

    Clark, I. E. et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162–1166 (2006).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003).

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Yang, Y. et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc. Natl Acad. Sci. USA 103, 10793–10798 (2006).

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Blesa, J. & Przedborski, S. Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front. Neuroanat. 8, 155 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

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

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Pickrell, A. M. et al. Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 87, 371–381 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. 115.

    Hsieh, C. H. et al. Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19, 709–724 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. 116.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Lahiri, V. & Klionsky, D. J. Functional impairment in RHOT1/Miro1 degradation and mitophagy is a shared feature in familial and sporadic Parkinson disease. Autophagy 13, 1259–1261 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Matheoud, D. et al. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016).

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Davis, C. H. et al. Transcellular degradation of axonal mitochondria. Proc. Natl Acad. Sci. USA 111, 9633–9638 (2014).

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Jin, G. et al. Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. Nat. Immunol. 19, 29–40 (2018).

    PubMed  Article  CAS  Google Scholar 

  121. 121.

    Yussman, M. G. et al. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat. Med. 8, 725–730 (2002).

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Zhang, J. & Ney, P. A. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16, 939–946 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123.

    Georgakopoulos, N. D., Wells, G. & Campanella, M. The pharmacological regulation of cellular mitophagy. Nat. Chem. Biol. 13, 136–146 (2017).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Hardie, D. G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes 62, 2164–2172 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125.

    Kim, J., Yang, G., Kim, Y., Kim, J. & Ha, J. AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med. 48, e224 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

    Johnson, S. C. et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342, 1524–1528 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Pan, T. et al. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 164, 541–551 (2009).

    PubMed  Article  CAS  Google Scholar 

  128. 128.

    Song, Y. M. et al. Metformin restores Parkin-mediated mitophagy, suppressed by cytosolic p53. Int. J. Mol. Sci. 17, 122 (2016).

    PubMed Central  Article  CAS  Google Scholar 

  129. 129.

    Hoshino, A. et al. Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic beta-cell function in diabetes. Proc. Natl Acad. Sci. USA 111, 3116–3121 (2014).

    PubMed  Article  CAS  Google Scholar 

  130. 130.

    Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  131. 131.

    Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  132. 132.

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    PubMed  Article  CAS  Google Scholar 

  133. 133.

    Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016).

    PubMed  Article  CAS  Google Scholar 

  134. 134.

    Xing, Y., Liqi, Z., Jian, L., Qinghua, Y. & Qian, Y. Doxycycline induces mitophagy and suppresses production of interferon-β in IPEC-J2 cells. Front. Cell. Infect. Microbiol. 7, 21 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. 135.

    Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566–581 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    Mouchiroud, L. et al. The NAD+/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    East, D. A. et al. PMI: a δPsim independent pharmacological regulator of mitophagy. Chem. Biol. 21, 1585–1596 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Jain, A. et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285, 22576–22591 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Jo, C. et al. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 5, 3496 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. 141.

    Holmstrom, K. M., Kostov, R. V. & Dinkova-Kostova, A. T. The multifaceted role of Nrf2 in mitochondrial function. Curr. Opin. Toxicol. 1, 80–91 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    De Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435–492 (1966).

    PubMed  Article  Google Scholar 

  143. 143.

    Hernandez, G. et al. MitoTimer: a novel tool for monitoring mitochondrial turnover. Autophagy 9, 1852–1861 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  145. 145.

    Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162–166 (2014).

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Kumar, A. et al. Parkin-phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity. Nat. Struct. Mol. Biol. 24, 475–483 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. 147.

    Mijaljica, D., Prescott, M. & Devenish, R. J. A fluorescence microscopy assay for monitoring mitophagy in the yeast Saccharomyces cerevisiae. J. Vis. Exp. 18, 2779 (2011).

    Google Scholar 

  148. 148.

    Riley, B. E. et al. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat. Commun. 4, 1982 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    Schubert, A. F. et al. Structure of PINK1 in complex with its substrate ubiquitin. Nature 552, 51–56 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  150. 150.

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

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

We apologize to those colleagues, whose work could not be referenced owing to space limitations. K.P. is supported by an AXA Research Fund post-doctoral long-term fellowship. E.L. is supported by a Scholarship for Strengthening Post-Doctoral Research from The Greek State Scholarships Foundation (IKY) within the framework of the Operational Programme “Human Resources Development Program, Education and Life-Long Learning”. Work in the authors’ laboratory is funded by grants from the European Research Council (ERC – GA695190 – MANNA, ERC – GA737599 – NeuronAgeScreen), the European Commission Framework Programmes, and the Greek Ministry of Education.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nektarios Tavernarakis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Palikaras, K., Lionaki, E. & Tavernarakis, N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 20, 1013–1022 (2018). https://doi.org/10.1038/s41556-018-0176-2

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing