Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline. Various quality control pathways, such as mitochondrial unfolded protein response (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy), respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria. This work provides a concise review of mechanisms by which disease-linked aberrant proteins affect mitochondrial function and an overview of mitochondrial quality control pathways that counteract mitochondrial proteotoxicity. We focus on mitochondrial quality control mechanisms relying on the Ub-mediated protein degradation, such as mitochondria-specific autophagy and the mitochondrial arm of the Ub proteasome system (UPS). We highlight the importance of a widening perspective of how these pathways protect mitochondria from proteotoxic stress to better understand mitochondrial proteotoxicity in overlapping pathophysiological pathways. Implications of these mechanisms in disease development are also briefly summarized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

N/A; no unpublished data is included.

References

  1. Zhao RZ, Jiang S, Zhang L, Yu ZB (2019) Mitochondrial electron transport chain, ROS generation and uncoupling (review). Int J Mol Med 44:3–15

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Wescott AP, Kao JPY, Lederer WJ, Boyman L (2019) Voltage-energized calcium-sensitive ATP production by mitochondria. Nat Metab 1:975–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pitt AS, Buchanan SK (2021) A biochemical and structural understanding of TOM complex interactions and implications for human health and disease. Cells 10:1164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem 288:27584–27593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang C, Youle RJ (2012) Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1’s inhibitory effect on Bak. Oncogene 31:3177–3189

    Article  CAS  PubMed  Google Scholar 

  8. Lopez J, Tait SW (2015) Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer 112:957–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kale J, Osterlund EJ, Andrews DW (2018) BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ 25:65–80

    Article  CAS  PubMed  Google Scholar 

  10. Kang W, Suzuki M, Saito T, Miyado K (2021) Emerging role of TCA cycle-related enzymes in human diseases. Int J Mol Sci 22:13057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eaton S, Bartlett K, Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320(Pt 2):345–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW (2010) Mitochondrial DNA mutations and human disease. Biochim Biophys Acta 1797:113–128

    Article  CAS  PubMed  Google Scholar 

  13. Vringer E, Tait SWG (2019) Mitochondria and inflammation: cell death heats up. Front Cell Dev Biol 7:100

    Article  PubMed  PubMed Central  Google Scholar 

  14. Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505:335–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nowinski SM, Solmonson A, Rusin SF, Maschek JA, Bensard CL, Fogarty S, Jeong MY, Lettlova S, Berg JA, Morgan JT, Ouyang Y, Naylor BC, Paulo JA, Funai K, Cox JE, Gygi SP, Winge DR, DeBerardinis RJ, Rutter J (2020) Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria. Elife. https://doi.org/10.7554/eLife.58041

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lill R, Freibert SA (2020) Mechanisms of mitochondrial iron-sulfur protein biogenesis. Annu Rev Biochem 89:471–499

    Article  CAS  PubMed  Google Scholar 

  18. Mesmin B (2016) Mitochondrial lipid transport and biosynthesis: a complex balance. J Cell Biol 214:9–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martin-Maestro P, Sproul A, Martinez H, Paquet D, Gerges M, Noggle S, Starkov AA (2019) Autophagy induction by bexarotene promotes mitophagy in presenilin 1 familial Alzheimer’s disease iPSC-derived neural stem cells. Mol Neurobiol 56:8220–8236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Watson JA, Lowenstein JM (1970) Citrate and the conversion of carbohydrate into fat. Fatty acid synthesis by a combination of cytoplasm and mitochondria. J Biol Chem 245:5993–6002

    Article  CAS  PubMed  Google Scholar 

  21. Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2:156–162

    Article  CAS  PubMed  Google Scholar 

  22. Karbowski M (2010) Mitochondria on guard: role of mitochondrial fusion and fission in the regulation of apoptosis. Adv Exp Med Biol 687:131–142

    Article  CAS  PubMed  Google Scholar 

  23. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, Korsmeyer SJ (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2:55–67

    Article  CAS  PubMed  Google Scholar 

  24. Burtscher J, Syed MMK, Keller MA, Lashuel HA, Millet GP (2021) Fatal attraction: the role of hypoxia when alpha-synuclein gets intimate with mitochondria. Neurobiol Aging 107:128–141

    Article  CAS  PubMed  Google Scholar 

  25. Jankovic M, Novakovic I, Gamil ADP, Gamil ADA, Drinic A, Abdel Motaleb FI, Ducic S, Nikolic D (2021) Current concepts on genetic aspects of mitochondrial dysfunction in amyotrophic lateral sclerosis. Int J Mol Sci 22:9832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Johri A (2021) Disentangling mitochondria in Alzheimer’s disease. Int J Mol Sci 22:11520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sawant N, Morton H, Kshirsagar S, Reddy AP, Reddy PH (2021) Mitochondrial abnormalities and synaptic damage in Huntington’s disease: a focus on defective mitophagy and mitochondria-targeted therapeutics. Mol Neurobiol. https://doi.org/10.1007/s12035-021-02556-x

    Article  PubMed  Google Scholar 

  28. Sonsky I, Vodicka P, Vodickova Kepkova K, Hansikova H (2021) Mitophagy in Huntington’s disease. Neurochem Int 149:105147

    Article  CAS  PubMed  Google Scholar 

  29. Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, Jiang S, Ma X, Jiang Z, da Rocha EL, Sheng M, Choi H, Lerou PH, Li H, Wang X (2016) The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med 22:869–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47:e147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thibaudeau TA, Anderson RT, Smith DM (2018) A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nat Commun 9:1097

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zheng C, Geetha T, Babu JR (2014) Failure of ubiquitin proteasome system: risk for neurodegenerative diseases. Neurodegener Dis 14:161–175

    Article  PubMed  Google Scholar 

  33. Zheng Q, Huang T, Zhang L, Zhou Y, Luo H, Xu H, Wang X (2016) Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci 8:303

    Article  PubMed  PubMed Central  Google Scholar 

  34. Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 25:5789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Knopman DS, Amieva H, Petersen RC, Chetelat G, Holtzman DM, Hyman BT, Nixon RA, Jones DT (2021) Alzheimer disease. Nat Rev Dis Primers 7:33

    Article  PubMed  PubMed Central  Google Scholar 

  36. Knopman DS, Jagust WJ (2021) Alzheimer disease spectrum: syndrome and etiology from clinical and PET imaging perspectives. Neurology 96:299–300

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Macdonald R, Barnes K, Hastings C, Mortiboys H (2018) Mitochondrial abnormalities in Parkinson’s disease and Alzheimer’s disease: can mitochondria be targeted therapeutically? Biochem Soc Trans 46:891–909

    Article  CAS  PubMed  Google Scholar 

  39. Pantiya P, Thonusin C, Chattipakorn N, Chattipakorn SC (2020) Mitochondrial abnormalities in neurodegenerative models and possible interventions: focus on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease. Mitochondrion 55:14–47

    Article  CAS  PubMed  Google Scholar 

  40. Swerdlow RH (2018) Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis 62:1403–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29:9090–9103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Terada T, Therriault J, Kang MS, Savard M, Pascoal TA, Lussier F, Tissot C, Wang YT, Benedet A, Poltronetti NM, Ottoy J, Arias JF, Bezgin G, Matsudaira T, Bunai T, Obi T, Tsukada H, Ouchi Y, Rosa-Neto P (2022) Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer’s disease. Eur J Neurol 29:1324–1334

    Article  PubMed  Google Scholar 

  43. Yao PJ, Eren E, Goetzl EJ, Kapogiannis D (2021) Mitochondrial electron transport chain protein abnormalities detected in plasma extracellular vesicles in Alzheimer’s disease. Biomedicines. 9:1587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD (2005) Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J 19:2040–2041

    Article  CAS  PubMed  Google Scholar 

  45. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15:1437–1449

    Article  CAS  PubMed  Google Scholar 

  46. Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M (2008) The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 105:13145–13150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, Wang C, Heman-Ackah SM, Hessa T, Guha R, Martin SE, Youle RJ (2013) High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504:291–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hu W, Wang Z, Zheng H (2018) Mitochondrial accumulation of amyloid beta (Abeta) peptides requires TOMM22 as a main Abeta receptor in yeast. J Biol Chem 293:12681–12689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK (2006) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 26:9057–9068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cenini G, Rub C, Bruderek M, Voos W (2016) Amyloid beta-peptides interfere with mitochondrial preprotein import competence by a coaggregation process. Mol Biol Cell 27:3257–3272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452

    Article  CAS  PubMed  Google Scholar 

  52. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Benatar M, Wuu J, Fernandez C, Weihl CC, Katzen H, Steele J, Oskarsson B, Taylor JP (2013) Motor neuron involvement in multisystem proteinopathy: implications for ALS. Neurology 80:1874–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chakrabarti L, Zahra R, Jackson SM, Kazemi-Esfarjani P, Sopher BL, Mason AG, Toneff T, Ryu S, Shaffer S, Kansy JW, Eng J, Merrihew G, MacCoss MJ, Murphy A, Goodlett DR, Hook V, Bennett CL, Pallanck LJ, La Spada AR (2010) Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration mice reveals a role for Nna proteins in neuronal bioenergetics. Neuron 66:835–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurro MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Consortium I, Galassi G, Scholz SW, Taylor JP, Restagno G, Chio A, Traynor BJ (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lin BC, Phung TH, Higgins NR, Greenslade JE, Prado MA, Finley D, Karbowski M, Polster BM, Monteiro MJ (2021) ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import. Hum Mol Genet 30:1230–1246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL (2020) TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell 183(636–649):e18

    Google Scholar 

  59. Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ (2020) The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med 52:1652–1662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Geuens T, Bouhy D, Timmerman V (2016) The hnRNP family: insights into their role in health and disease. Hum Genet 135:851–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611

    Article  CAS  PubMed  Google Scholar 

  62. Davis SA, Itaman S, Khalid-Janney CM, Sherard JA, Dowell JA, Cairns NJ, Gitcho MA (2018) TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics. Neurosci Lett 678:8–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang P, Deng J, Dong J, Liu J, Bigio EH, Mesulam M, Wang T, Sun L, Wang L, Lee AY, McGee WA, Chen X, Fushimi K, Zhu L, Wu JY (2019) TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet 15:e1007947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa M (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4:124–134

    Article  CAS  PubMed  Google Scholar 

  65. Shimizu T, Kozuka Y, Kusano M, Nagane M, Yamashita T, Hachiya N (2020) PrP (122–139) is a covert mitochondrial targeting signal of prion protein and it specifically triggers the perinuclear clustering of mitochondria in neuronal culture cells. Biochem Biophys Res Commun 524:301–307

    Article  CAS  PubMed  Google Scholar 

  66. Laurents DV, Stuani C, Pantoja-Uceda D, Buratti E, Mompean M (2021) Aromatic and aliphatic residues of the disordered region of TDP-43 are on a fast track for self-assembly. Biochem Biophys Res Commun 578:110–114

    Article  CAS  PubMed  Google Scholar 

  67. Xu S, Peng G, Wang Y, Fang S, Karbowski M (2011) The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol Biol Cell 22:291–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang KY, Yang S, Warraich ST, Blair IP (2014) Ubiquilin 2: a component of the ubiquitin-proteasome system with an emerging role in neurodegeneration. Int J Biochem Cell Biol 50:123–126

    Article  CAS  PubMed  Google Scholar 

  70. Itakura E, Zavodszky E, Shao S, Wohlever ML, Keenan RJ, Hegde RS (2016) Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation. Mol Cell 63:21–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bates G (2003) Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 361:1642–1644

    Article  CAS  PubMed  Google Scholar 

  72. Finkbeiner S (2011) Huntington’s disease. Cold Spring Harb Perspect Biol 3:a007476

    Article  PubMed  PubMed Central  Google Scholar 

  73. Shirasaki DI, Greiner ER, Al-Ramahi I, Gray M, Boontheung P, Geschwind DH, Botas J, Coppola G, Horvath S, Loo JA, Yang XW (2012) Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 75:41–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pickrell AM, Fukui H, Wang X, Pinto M, Moraes CT (2011) The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions. J Neurosci 31:9895–9904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang H, Lim PJ, Karbowski M, Monteiro MJ (2009) Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18:737–752

    Article  CAS  PubMed  Google Scholar 

  76. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17:377–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Squitieri F, Falleni A, Cannella M, Orobello S, Fulceri F, Lenzi P, Fornai F (2010) Abnormal morphology of peripheral cell tissues from patients with Huntington disease. J Neural Transm (Vienna) 117:77–83

    Article  PubMed  Google Scholar 

  78. Oliveira JM (2010) Nature and cause of mitochondrial dysfunction in Huntington’s disease: focusing on huntingtin and the striatum. J Neurochem 114:1–12

    CAS  PubMed  Google Scholar 

  79. Yablonska S, Ganesan V, Ferrando LM, Kim J, Pyzel A, Baranova OV, Khattar NK, Larkin TM, Baranov SV, Chen N, Strohlein CE, Stevens DA, Wang X, Chang YF, Schurdak ME, Carlisle DL, Minden JS, Friedlander RM (2019) Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23. Proc Natl Acad Sci USA 116:16593–16602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Guedes-Dias P, de Proenca J, Soares TR, Leitao-Rocha A, Pinho BR, Duchen MR, Oliveira JM (2015) HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons. Biochim Biophys Acta 1852:2484–2493

    Article  CAS  PubMed  Google Scholar 

  81. Pellman JJ, Hamilton J, Brustovetsky T, Brustovetsky N (2015) Ca(2+) handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington’s disease. J Neurochem 134:652–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bozzi M, Sciandra F (2020) Molecular mechanisms underlying muscle wasting in Huntington’s disease. Int J Mol Sci 21:8314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Stanga S, Caretto A, Boido M, Vercelli A (2020) Mitochondrial dysfunctions: a red thread across neurodegenerative diseases. Int J Mol Sci 21:3719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gonzalez-Rodriguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, Tkatch T, Stavarache MA, Wokosin DL, Gao L, Kaplitt MG, Lopez-Barneo J, Schumacker PT, Surmeier DJ (2021) Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599:650–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Picca A, Guerra F, Calvani R, Romano R, Coelho-Junior HJ, Bucci C, Marzetti E (2021) Mitochondrial dysfunction, protein misfolding and neuroinflammation in Parkinson’s disease: roads to biomarker discovery. Biomolecules 11:1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Narendra D, Tanaka A, Suen DF, Youle RJ (2009) Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy 5:706–708

    Article  CAS  PubMed  Google Scholar 

  89. Agarwal S, Muqit MMK (2021) PTEN-induced kinase 1 (PINK1) and Parkin: unlocking a mitochondrial quality control pathway linked to Parkinson’s disease. Curr Opin Neurobiol 72:111–119

    Article  PubMed  Google Scholar 

  90. Karbowski M, Youle RJ (2011) Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr Opin Cell Biol 23:476–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Nicoletti V, Palermo G, Del Prete E, Mancuso M, Ceravolo R (2021) Understanding the multiple role of mitochondria in Parkinson’s disease and related disorders: lesson from genetics and protein-interaction network. Front Cell Dev Biol 9:636506

    Article  PubMed  PubMed Central  Google Scholar 

  92. Palikaras K, Lionaki E, Tavernarakis N (2018) Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 20:1013–1022

    Article  CAS  PubMed  Google Scholar 

  93. Hofmann C, Katus HA, Doroudgar S (2019) Protein misfolding in cardiac disease. Circulation 139:2085–2088

    Article  PubMed  Google Scholar 

  94. Pattison JS, Robbins J (2008) Protein misfolding and cardiac disease: establishing cause and effect. Autophagy 4:821–823

    Article  CAS  PubMed  Google Scholar 

  95. McLendon PM, Robbins J (2011) Desmin-related cardiomyopathy: an unfolding story. Am J Physiol Heart Circ Physiol 301:H1220–H1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Schroder R, Schoser B (2009) Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol 19:483–492

    Article  PubMed  PubMed Central  Google Scholar 

  97. Paulin D, Li Z (2004) Desmin: a major intermediate filament protein essential for the structural integrity and function of muscle. Exp Cell Res 301:1–7

    Article  CAS  PubMed  Google Scholar 

  98. Kedia N, Arhzaouy K, Pittman SK, Sun Y, Batchelor M, Weihl CC, Bieschke J (2019) Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers. Proc Natl Acad Sci USA 116:16835–16840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Winter L, Wittig I, Peeva V, Eggers B, Heidler J, Chevessier F, Kley RA, Barkovits K, Strecker V, Berwanger C, Herrmann H, Marcus K, Kornblum C, Kunz WS, Schroder R, Clemen CS (2016) Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue. Acta Neuropathol 132:453–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Alam S, Abdullah CS, Aishwarya R, Miriyala S, Panchatcharam M, Peretik JM, Orr AW, James J, Robbins J, Bhuiyan MS (2018) Aberrant mitochondrial fission is maladaptive in desmin mutation-induced cardiac proteotoxicity. J Am Heart Assoc. https://doi.org/10.1161/JAHA.118.009289

    Article  PubMed  PubMed Central  Google Scholar 

  101. Bhuiyan MS, Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins J (2013) Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest 123:5284–5297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dayal AA, Medvedeva NV, Nekrasova TM, Duhalin SD, Surin AK, Minin AA (2020) Desmin interacts directly with mitochondria. Int J Mol Sci 21:8122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Park JH, Kim DH, Park YG, Kwon DY, Choi M, Jung JH, Han K (2020) Association of Parkinson disease with risk of cardiovascular disease and all-cause mortality: a nationwide, population-based cohort study. Circulation 141:1205–1207

    Article  PubMed  Google Scholar 

  104. Scorza FA, Fiorini AC, Scorza CA, Finsterer J (2018) Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci 53:1–5

    Article  PubMed  Google Scholar 

  105. Piqueras-Flores J, Lopez-Garcia A, Moreno-Reig A, Gonzalez-Martinez A, Hernandez-Gonzalez A, Vaamonde-Gamo J, Jurado-Roman A (2018) Structural and functional alterations of the heart in Parkinson’s disease. Neurol Res 40:53–61

    Article  PubMed  Google Scholar 

  106. Kubli DA, Zhang X, Lee Y, Hanna RA, Quinsay MN, Nguyen CK, Jimenez R, Petrosyan S, Murphy AN, Gustafsson AB (2013) Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J Biol Chem 288:915–926

    Article  CAS  PubMed  Google Scholar 

  107. Song M, Gong G, Burelle Y, Gustafsson AB, Kitsis RN, Matkovich SJ, Dorn GW 2nd (2015) Interdependence of Parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. Circ Res 117:346–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Dorn GW 2nd (2016) Parkin-dependent mitophagy in the heart. J Mol Cell Cardiol 95:42–49

    Article  CAS  PubMed  Google Scholar 

  109. Gottlieb RA, Piplani H, Sin J, Sawaged S, Hamid SM, Taylor DJ, de Freitas Germano J (2021) At the heart of mitochondrial quality control: many roads to the top. Cell Mol Life Sci 78:3791–3801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, Simonson DC, Testa MA, Weiss R (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019

    Article  PubMed  Google Scholar 

  111. Sha W, Hu F, Bu S (2020) Mitochondrial dysfunction and pancreatic islet beta-cell failure (review). Exp Ther Med 20:266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Westermark P, Wernstedt C, Wilander E, Hayden DW, O’Brien TD, Johnson KH (1987) Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA 84:3881–3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Westermark P (1972) Quantitative studies on amyloid in the islets of Langerhans. Ups J Med Sci 77:91–94

    Article  CAS  PubMed  Google Scholar 

  114. Hull RL, Westermark GT, Westermark P, Kahn SE (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 89:3629–3643

    Article  CAS  PubMed  Google Scholar 

  115. Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery MJ, Guilhaus M, Ittner LM, Eckert A, Gotz J (2010) Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction. Proteomics 10:1621–1633

    Article  CAS  PubMed  Google Scholar 

  116. Pearson G, Soleimanpour SA (2018) A ubiquitin-dependent mitophagy complex maintains mitochondrial function and insulin secretion in beta cells. Autophagy 14:1160–1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hernandez MG, Aguilar AG, Burillo J, Oca RG, Manca MA, Novials A, Alcarraz-Vizan G, Guillen C, Benito M (2018) Pancreatic beta cells overexpressing hIAPP impaired mitophagy and unbalanced mitochondrial dynamics. Cell Death Dis 9:481

    Article  PubMed  PubMed Central  Google Scholar 

  118. Tyynismaa H, Ylikallio E, Patel M, Molnar MJ, Haller RG, Suomalainen A (2009) A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet 85:290–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA 101:9103–9108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Smits P, Smeitink J, van den Heuvel L (2010) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010:737385

    Article  PubMed  PubMed Central  Google Scholar 

  121. Sheth A, Escobar-Alvarez S, Gardner J, Ran L, Heaney ML, Scheinberg DA (2014) Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers. Cell Death Dis 5:e1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Battersby BJ, Richter U (2013) Why translation counts for mitochondria - retrograde signalling links mitochondrial protein synthesis to mitochondrial biogenesis and cell proliferation. J Cell Sci 126:4331–4338

    Article  CAS  PubMed  Google Scholar 

  123. Suhm T, Kaimal JM, Dawitz H, Peselj C, Masser AE, Hanzen S, Ambrozic M, Smialowska A, Bjorck ML, Brzezinski P, Nystrom T, Buttner S, Andreasson C, Ott M (2018) Mitochondrial translation efficiency controls cytoplasmic protein homeostasis. Cell Metab 27:1309-1322 e6

    Article  CAS  PubMed  Google Scholar 

  124. Breitenbach M, Rinnerthaler M, Hartl J, Stincone A, Vowinckel J, Breitenbach-Koller H, Ralser M (2014) Mitochondria in ageing: there is metabolism beyond the ROS. FEMS Yeast Res 14:198–212

    Article  CAS  PubMed  Google Scholar 

  125. Caballero A, Ugidos A, Liu B, Oling D, Kvint K, Hao X, Mignat C, Nachin L, Molin M, Nystrom T (2011) Absence of mitochondrial translation control proteins extends life span by activating sirtuin-dependent silencing. Mol Cell 42:390–400

    Article  CAS  PubMed  Google Scholar 

  126. Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, Hurren R, Jitkova Y, Gronda M, Maclean N, Lai CK, Eberhard Y, Bartoszko J, Spagnuolo P, Rutledge AC, Datti A, Ketela T, Moffat J, Robinson BH, Cameron JH, Wrana J, Eaves CJ, Minden MD, Wang JC, Dick JE, Humphries K, Nislow C, Giaever G, Schimmer AD (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20:674–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Richter U, Lahtinen T, Marttinen P, Myohanen M, Greco D, Cannino G, Jacobs HT, Lietzen N, Nyman TA, Battersby BJ (2013) A mitochondrial ribosomal and RNA decay pathway blocks cell proliferation. Curr Biol 23:535–541

    Article  CAS  PubMed  Google Scholar 

  128. Richter U, Lahtinen T, Marttinen P, Suomi F, Battersby BJ (2015) Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness. J Cell Biol 211:373–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Burman JL, Pickles S, Wang C, Sekine S, Vargas JNS, Zhang Z, Youle AM, Nezich CL, Wu X, Hammer JA, Youle RJ (2017) Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Biol 216:3231–3247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktaschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA (2019) Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 22:401–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Fiesel FC, James ED, Hudec R, Springer W (2017) Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy. Oncotarget 8:106233–106248

    Article  PubMed  PubMed Central  Google Scholar 

  132. Munch C, Harper JW (2016) Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 534:710–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Siegelin MD, Dohi T, Raskett CM, Orlowski GM, Powers CM, Gilbert CA, Ross AH, Plescia J, Altieri DC (2011) Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J Clin Invest 121:1349–1360

    Article  PubMed  PubMed Central  Google Scholar 

  134. Bernstein SH, Venkatesh S, Li M, Lee J, Lu B, Hilchey SP, Morse KM, Metcalfe HM, Skalska J, Andreeff M, Brookes PS, Suzuki CK (2012) The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood 119:3321–3329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dong J, Zhang KJ, Li GC, Chen XR, Lin JJ, Li JW, Lv ZY, Deng ZZ, Dai J, Cao W, Jiang Q (2021) CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-021-00782-6

    Article  PubMed  PubMed Central  Google Scholar 

  136. Zhao Q, Wang J, Levichkin IV, Stasinopoulos S, Ryan MT, Hoogenraad NJ (2002) A mitochondrial specific stress response in mammalian cells. EMBO J 21:4411–4419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bezawork-Geleta A, Brodie EJ, Dougan DA, Truscott KN (2015) LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins. Sci Rep 5:17397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mevissen TET, Komander D (2017) Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem 86:159–192

    Article  CAS  PubMed  Google Scholar 

  139. Stach L, Freemont PS (2017) The AAA+ ATPase p97, a cellular multitool. Biochem J 474:2953–2976

    Article  CAS  PubMed  Google Scholar 

  140. Karbowski M, Neutzner A, Youle RJ (2007) The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178:71–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yonashiro R, Ishido S, Kyo S, Fukuda T, Goto E, Matsuki Y, Ohmura-Hoshino M, Sada K, Hotta H, Yamamura H, Inatome R, Yanagi S (2006) A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO J 25:3618–3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Benard G, Neutzner A, Peng G, Wang C, Livak F, Youle RJ, Karbowski M (2010) IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation. EMBO J 29:1458–1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Di Rita A, Peschiaroli A, D’Acunzo P, Strobbe D, Hu Z, Gruber J, Nygaard M, Lambrughi M, Melino G, Papaleo E, Dengjel J, El Alaoui S, Campanella M, Dotsch V, Rogov VV, Strappazzon F, Cecconi F (2018) HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha. Nat Commun 9:3755

    Article  PubMed  PubMed Central  Google Scholar 

  144. Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS, Sheng M (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510:370–375

    Article  CAS  PubMed  Google Scholar 

  145. Liang JR, Martinez A, Lane JD, Mayor U, Clague MJ, Urbe S (2015) USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death. EMBO Rep 16:618–627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Nakamura N, Hirose S (2008) Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol Biol Cell 19:1903–1911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, Maecker H, O’Rourke K, Bazan F, Eastham-Anderson J, Yue P, Dornan D, Huang DC, Dixit VM (2010) Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463:103–107

    Article  CAS  PubMed  Google Scholar 

  148. McLelland GL, Goiran T, Yi W, Dorval G, Chen CX, Lauinger ND, Krahn AI, Valimehr S, Rakovic A, Rouiller I, Durcan TM, Trempe JF, Fon EA (2018) Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. Elife. https://doi.org/10.7554/eLife.32866

    Article  PubMed  PubMed Central  Google Scholar 

  149. Castanzo DT, LaFrance B, Martin A (2020) The AAA+ ATPase Msp1 is a processive protein translocase with robust unfoldase activity. Proc Natl Acad Sci USA 117:14970–14977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Chen YC, Umanah GK, Dephoure N, Andrabi SA, Gygi SP, Dawson TM, Dawson VL, Rutter J (2014) Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. EMBO J 33:1548–1564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Okreglak V, Walter P (2014) The conserved AAA-ATPase Msp1 confers organelle specificity to tail-anchored proteins. Proc Natl Acad Sci USA 111:8019–8024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W (2011) SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471:104–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Neutzner A, Li S, Xu S, Karbowski M (2012) The ubiquitin/proteasome system-dependent control of mitochondrial steps in apoptosis. Semin Cell Dev Biol 23:499–508

    Article  CAS  PubMed  Google Scholar 

  154. Zhang B, Huang J, Li HL, Liu T, Wang YY, Waterman P, Mao AP, Xu LG, Zhai Z, Liu D, Marrack P, Shu HB (2008) GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth. Cell Res 18:900–910

    Article  CAS  PubMed  Google Scholar 

  155. Braschi E, Zunino R, McBride HM (2009) MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 10:748–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Xu S, Cherok E, Das S, Li S, Roelofs BA, Ge SX, Polster BM, Boyman L, Lederer WJ, Wang C, Karbowski M (2016) Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein. Mol Biol Cell 27:349–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL, Hess S, Chan DC (2011) Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 20:1726–1737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205:143–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510:162–166

    Article  CAS  PubMed  Google Scholar 

  160. Koyano F, Yamano K, Kosako H, Tanaka K, Matsuda N (2019) Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL. J Biol Chem. https://doi.org/10.1074/jbc.RA118.006302

    Article  PubMed  PubMed Central  Google Scholar 

  161. Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci USA 105:11364–11369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298

    Article  PubMed  PubMed Central  Google Scholar 

  163. McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F, Burel S, Balk K, Kumar A, Montava-Garriga L, Prescott AR, Hassoun SM, Mouton-Liger F, Ball G, Hills R, Knebel A, Ulusoy A, Di Monte DA, Tamjar J, Antico O, Fears K, Smith L, Brambilla R, Palin E, Valori M, Eerola-Rautio J, Tienari P, Corti O, Dunnett SB, Ganley IG, Suomalainen A, Muqit MMK (2018) Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. Open Biol. https://doi.org/10.1098/rsob.180108

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206:655–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Eiyama A, Okamoto K (2015) PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol 33:95–101

    Article  CAS  PubMed  Google Scholar 

  167. Jian F, Chen D, Chen L, Yan C, Lu B, Zhu Y, Chen S, Shi A, Chan DC, Song Z (2018) Sam50 regulates PINK1-Parkin-mediated mitophagy by controlling PINK1 stability and mitochondrial morphology. Cell Rep 23:2989–3005

    Article  CAS  PubMed  Google Scholar 

  168. Chan NC, Lithgow T (2008) The peripheral membrane subunits of the SAM complex function codependently in mitochondrial outer membrane biogenesis. Mol Biol Cell 19:126–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Abudu YP, Shrestha BK, Zhang W, Palara A, Brenne HB, Larsen KB, Wolfson DL, Dumitriu G, Oie CI, Ahluwalia BS, Levy G, Behrends C, Tooze SA, Mouilleron S, Lamark T, Johansen T (2021) SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components. J Cell Biol 220:e202009092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Birgisdottir AB, Lamark T, Johansen T (2013) The LIR motif - crucial for selective autophagy. J Cell Sci 126:3237–3247

    Article  CAS  PubMed  Google Scholar 

  171. Lee JJ, Sanchez-Martinez A, Zarate AM, Beninca C, Mayor U, Clague MJ, Whitworth AJ (2018) Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin. J Cell Biol 217:1613–1622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. McWilliams TG, Prescott AR, Montava-Garriga L, Ball G, Singh F, Barini E, Muqit MMK, Brooks SP, Ganley IG (2018) Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab 27(439–449):e5

    Google Scholar 

  173. Perez FA, Palmiter RD (2005) Parkin-deficient mice are not a robust model of Parkinsonism. Proc Natl Acad Sci USA 102:2174–2179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Kageyama Y, Hoshijima M, Seo K, Bedja D, Sysa-Shah P, Andrabi SA, Chen W, Hoke A, Dawson VL, Dawson TM, Gabrielson K, Kass DA, Iijima M, Sesaki H (2014) Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J 33:2798–2813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Yamada T, Murata D, Adachi Y, Itoh K, Kameoka S, Igarashi A, Kato T, Araki Y, Huganir RL, Dawson TM, Yanagawa T, Okamoto K, Iijima M, Sesaki H (2018) Mitochondrial stasis reveals p62-mediated ubiquitination in Parkin-independent mitophagy and mitigates nonalcoholic fatty liver disease. Cell Metab 28(588–604):e5

    Google Scholar 

  176. Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12:2245–2256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zheng YT, Shahnazari S, Brech A, Lamark T, Johansen T, Brumell JH (2009) The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J Immunol 183:5909–5916

    Article  CAS  PubMed  Google Scholar 

  179. Prabakaran T, Bodda C, Krapp C, Zhang BC, Christensen MH, Sun C, Reinert L, Cai Y, Jensen SB, Skouboe MK, Nyengaard JR, Thompson CB, Lebbink RJ, Sen GC, van Loo G, Nielsen R, Komatsu M, Nejsum LN, Jakobsen MR, Gyrd-Hansen M, Paludan SR (2018) Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J 37:e97858

    Article  PubMed  PubMed Central  Google Scholar 

  180. Sanchez-Martin P, Saito T, Komatsu M (2019) p62/SQSTM1: “Jack of all trades” in health and cancer. FEBS J 286:8–23

    Article  CAS  PubMed  Google Scholar 

  181. Tan CT, Soh NJH, Chang HC, Yu VC (2021) p62/SQSTM1 in liver diseases: the usual suspect with multifarious identities. FEBS J. https://doi.org/10.1111/febs.16317

    Article  PubMed  Google Scholar 

  182. Lin XH, Qiu BQ, Ma M, Zhang R, Hsu SJ, Liu HH, Chen J, Gao DM, Cui JF, Ren ZG, Chen RX (2020) Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia. Oncogenesis 9:67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Oshima Y, Cartier E, Boyman L, Verhoeven N, Polster BM, Huang W, Kane M, Lederer WJ, Karbowski M (2021) Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination. J Cell Biol 220:e202006043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Villa E, Proics E, Rubio-Patino C, Obba S, Zunino B, Bossowski JP, Rozier RM, Chiche J, Mondragon L, Riley JS, Marchetti S, Verhoeyen E, Tait SWG, Ricci JE (2017) Parkin-independent mitophagy controls chemotherapeutic response in cancer cells. Cell Rep 20:2846–2859

    Article  CAS  PubMed  Google Scholar 

  185. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW (2013) Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496:372–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yoshii SR, Kishi C, Ishihara N, Mizushima N (2011) Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem 286:19630–19640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia GM, Campello S, Nardacci R, Piacentini M, Campanella M, Cecconi F (2015) AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ 22:419–432

    Article  CAS  PubMed  Google Scholar 

  188. Igarashi R, Yamashita SI, Yamashita T, Inoue K, Fukuda T, Fukuchi T, Kanki T (2020) Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1. Sci Rep 10:1465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Yamada A, Hikichi M, Nozawa T, Nakagawa I (2021) FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan. EMBO Rep 22:e52584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Pei G, Buijze H, Liu H, Moura-Alves P, Goosmann C, Brinkmann V, Kawabe H, Dorhoi A, Kaufmann SHE (2017) The E3 ubiquitin ligase NEDD4 enhances killing of membrane-perturbing intracellular bacteria by promoting autophagy. Autophagy 13:2041–2055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ji H, Wang J, Muid D, Song W, Jiang Y, Zhou H (2022) FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury. Cell Signal 92:110249

    Article  CAS  PubMed  Google Scholar 

  192. Li G, Li J, Shao R, Zhao J, Chen M (2021) FUNDC1: a promising mitophagy regulator at the mitochondria-associated membrane for cardiovascular diseases. Front Cell Dev Biol 9:788634

    Article  PubMed  PubMed Central  Google Scholar 

  193. Liu H, Zang C, Yuan F, Ju C, Shang M, Ning J, Yang Y, Ma J, Li G, Bao X, Zhang D (2022) The role of FUNDC1 in mitophagy, mitochondrial dynamics and human diseases. Biochem Pharmacol 197:114891

    Article  CAS  PubMed  Google Scholar 

  194. Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, Chen Q (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 14:177–185

    Article  PubMed  Google Scholar 

  195. Liu L, Li Y, Chen Q (2021) The emerging role of FUNDC1-mediated mitophagy in cardiovascular diseases. Front Physiol 12:807654

    Article  PubMed  PubMed Central  Google Scholar 

  196. Cai Y, Yang E, Yao X, Zhang X, Wang Q, Wang Y, Liu J, Fan W, Yi K, Kang C, Wu J (2021) FUNDC1-dependent mitophagy induced by tPA protects neurons against cerebral ischemia-reperfusion injury. Redox Biol 38:101792

    Article  CAS  PubMed  Google Scholar 

  197. Wang L, Wang P, Dong H, Wang S, Chu H, Yan W, Zhang X (2018) Ulk1/FUNDC1 prevents nerve cells from hypoxia-induced apoptosis by promoting cell autophagy. Neurochem Res 43:1539–1548

    Article  CAS  PubMed  Google Scholar 

  198. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, Chen Q (2014) A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell 54:362–377

    Article  CAS  PubMed  Google Scholar 

  199. Feng D, Liu L, Zhu Y, Chen Q (2013) Molecular signaling toward mitophagy and its physiological significance. Exp Cell Res 319:1697–1705

    Article  CAS  PubMed  Google Scholar 

  200. Li Y, Xue Y, Xu X, Wang G, Liu Y, Wu H, Li W, Wang Y, Chen Z, Zhang W, Zhu Y, Ji W, Xu T, Liu L, Chen Q (2019) A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity. EMBO J 38:e98786

    Article  PubMed  Google Scholar 

  201. Sulkshane P, Duek I, Ram J, Thakur A, Reis N, Ziv T, Glickman MH (2020) Inhibition of proteasome reveals basal mitochondrial ubiquitination. J Proteom 229:103949

    Article  CAS  Google Scholar 

  202. Radke S, Chander H, Schafer P, Meiss G, Kruger R, Schulz JB, Germain D (2008) Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi. J Biol Chem 283:12681–12685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Bragoszewski P, Wasilewski M, Sakowska P, Gornicka A, Bottinger L, Qiu J, Wiedemann N, Chacinska A (2015) Retro-translocation of mitochondrial intermembrane space proteins. Proc Natl Acad Sci USA 112:7713–7718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Clarke KJ, Adams AE, Manzke LH, Pearson TW, Borchers CH, Porter RK (2012) A role for ubiquitinylation and the cytosolic proteasome in turnover of mitochondrial uncoupling protein 1 (UCP1). Biochim Biophys Acta 1817:1759–1767

    Article  CAS  PubMed  Google Scholar 

  205. Bragoszewski P, Gornicka A, Sztolsztener ME, Chacinska A (2013) The ubiquitin-proteasome system regulates mitochondrial intermembrane space proteins. Mol Cell Biol 33:2136–2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Mohanraj K, Wasilewski M, Beninca C, Cysewski D, Poznanski J, Sakowska P, Bugajska Z, Deckers M, Dennerlein S, Fernandez-Vizarra E, Rehling P, Dadlez M, Zeviani M, Chacinska A (2019) Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7. EMBO Mol Med 11:e9561

    Article  PubMed  PubMed Central  Google Scholar 

  207. Vande Walle L, Lamkanfi M, Vandenabeele P (2008) The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ 15:453–460

    Article  CAS  PubMed  Google Scholar 

  208. Martinez Lyons A, Ardissone A, Reyes A, Robinson AJ, Moroni I, Ghezzi D, Fernandez-Vizarra E, Zeviani M (2016) COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency. J Med Genet 53:846–849

    Article  PubMed  Google Scholar 

  209. Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S (2006) MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 7:1019–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Yonashiro R, Sugiura A, Miyachi M, Fukuda T, Matsushita N, Inatome R, Ogata Y, Suzuki T, Dohmae N, Yanagi S (2009) Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation. Mol Biol Cell 20:4524–4530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Sugiura A, Yonashiro R, Fukuda T, Matsushita N, Nagashima S, Inatome R, Yanagi S (2011) A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein. Mitochondrion 11:139–146

    Article  CAS  PubMed  Google Scholar 

  212. Yoo YS, Park YJ, Lee HS, Oanh NTK, Cho MY, Heo J, Lee ES, Cho H, Park YY, Cho H (2019) Mitochondria ubiquitin ligase, MARCH5 resolves hepatitis B virus X protein aggregates in the liver pathogenesis. Cell Death Dis 10:938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Hussain M, Mohammed A, Saifi S, Khan A, Kaur E, Priya S, Agarwal H, Sengupta S (2021) MITOL-dependent ubiquitylation negatively regulates the entry of PolgammaA into mitochondria. PLoS Biol 19:e3001139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Shiiba I, Takeda K, Nagashima S, Ito N, Tokuyama T, Yamashita SI, Kanki T, Komatsu T, Urano Y, Fujikawa Y, Inatome R, Yanagi S (2021) MITOL promotes cell survival by degrading Parkin during mitophagy. EMBO Rep 22:e49097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Koyano F, Yamano K, Kosako H, Kimura Y, Kimura M, Fujiki Y, Tanaka K, Matsuda N (2019) Parkin-mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes. EMBO Rep 20:e47728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Chapman E, Maksim N, de la Cruz F, La Clair JJ (2015) Inhibitors of the AAA+ chaperone p97. Molecules 20:3027–3049

    Article  PubMed  PubMed Central  Google Scholar 

  217. Muller JM, Deinhardt K, Rosewell I, Warren G, Shima DT (2007) Targeted deletion of p97 (VCP/CDC48) in mouse results in early embryonic lethality. Biochem Biophys Res Commun 354:459–465

    Article  CAS  PubMed  Google Scholar 

  218. Shorter J, Houry WA (2018) Editorial: the role of AAA+ proteins in protein repair and degradation. Front Mol Biosci 5:85

    Article  PubMed  PubMed Central  Google Scholar 

  219. Ye Y, Meyer HH, Rapoport TA (2003) Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol 162:71–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Kimonis VE, Kovach MJ, Waggoner B, Leal S, Salam A, Rimer L, Davis K, Khardori R, Gelber D (2000) Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet Med 2:232–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Gonzalez MA, Feely SM, Speziani F, Strickland AV, Danzi M, Bacon C, Lee Y, Chou TF, Blanton SH, Weihl CC, Zuchner S, Shy ME (2014) A novel mutation in VCP causes charcot-marie-tooth type 2 disease. Brain 137:2897–2902

    Article  PubMed  PubMed Central  Google Scholar 

  222. Tang WK, Xia D (2016) Mutations in the human AAA(+) Chaperone p97 and related diseases. Front Mol Biosci 3:79

    Article  PubMed  PubMed Central  Google Scholar 

  223. Fang L, Hemion C, Pinho FB, Bippes CC, Flammer J, Neutzner A (2015) Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control. Front Cell Neurosci 9:16

    Article  PubMed  PubMed Central  Google Scholar 

  224. Bento AC, Bippes CC, Kohler C, Hemion C, Frank S, Neutzner A (2018) UBXD1 is a mitochondrial recruitment factor for p97/VCP and promotes mitophagy. Sci Rep 8:12415

    Article  PubMed  PubMed Central  Google Scholar 

  225. Weidberg H, Amon A (2018) MitoCPR-A surveillance pathway that protects mitochondria in response to protein import stress. Science. https://doi.org/10.1126/science.aan4146

    Article  PubMed  PubMed Central  Google Scholar 

  226. Levine CG, Mitra D, Sharma A, Smith CL, Hegde RS (2005) The efficiency of protein compartmentalization into the secretory pathway. Mol Biol Cell 16:279–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Chakrabarti O, Hegde RS (2009) Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration. Cell 137:1136–1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Sugiura A, Mattie S, Prudent J, McBride HM (2017) Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes. Nature 542:251–254

    Article  CAS  PubMed  Google Scholar 

  229. Weathington NM, Mallampalli RK (2014) Emerging therapies targeting the ubiquitin proteasome system in cancer. J Clin Invest 124:6–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Figures were created using BioRender.com and exported with an Academic License.

Funding

This work was supported by the National Institutes of Health under Award Number R01GM129584 (MK) and in part by the Center for Biomedical Engineering and Technology (BioMET).

Author information

Authors and Affiliations

  1. Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 111 S. Penn St., Suite 104, Baltimore, MD, 21201, USA

    Mariusz Karbowski, Yumiko Oshima & Nicolas Verhoeven

  2. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA

    Mariusz Karbowski, Yumiko Oshima & Nicolas Verhoeven

  3. University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Mariusz Karbowski

Authors
  1. Mariusz Karbowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yumiko Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolas Verhoeven
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MK wrote the first draft, YO and NV worked on subsequent drafts of the manuscript.

Corresponding author

Correspondence to Mariusz Karbowski.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

N/A; this is a review manuscript.

Consent for publication

The authors give their consent to publish this work in Cellular and Molecular Life Sciences.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karbowski, M., Oshima, Y. & Verhoeven, N. Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms. Cell. Mol. Life Sci. 79, 574 (2022). https://doi.org/10.1007/s00018-022-04604-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04604-8

Keywords

Search

Navigation