[en] PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.Abbreviations: ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATAD3A: ATPase family AAA domain containing 3A; BCL2L1/BCL-xL: BCL2 like 1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMA1: OMA1 zinc metallopeptidase; OMM: outer mitochondrial membrane; PARL: presenilin associated rhomboid like; PARP: poly(ADP-ribose) polymerase; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; SDHA: succinate dehydrogenase complex flavoprotein subunit A; TOMM70: translocase of outer mitochondrial membrane 70.
Disciplines :
Human health sciences: Multidisciplinary, general & others
Author, co-author :
Di Rienzo, Martina; Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National
Romagnoli, Alessandra; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Ciccosanti, Fabiola; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy. > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Refolo, Giulia; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Consalvi, Veronica; University of Rome "Sapienza", Rome, Italy > Department of Molecular Medicine
ARENA, Giuseppe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Valente, Enza Maria; University of Pavia, Pavia, Italy > Department of Molecular Medicine
Piacentini, Mauro; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
Fimia, Gian Maria; National Institute for Infectious Diseases Irccs "L. Spallanzani", Rome, Italy > Department of Epidemiology, Preclinical Research and Advanced Diagnostics
External co-authors :
yes
Language :
English
Title :
AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability
Publication date :
August 2022
Journal title :
Autophagy
ISSN :
1554-8627
eISSN :
1554-8635
Publisher :
Landes Bioscience, Georgetown, United States - Texas
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Killackey SA, Philpott DJ, Girardin SE. Mitophagy pathways in health and disease. J Cell Biol. 2020; 219. DOI: 10.1083/jcb.202004029
Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron. 2015; 85: 257–273.
Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018; 20: 1013–1022.
Pickles S, Vigie P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018; 28: R170–R185.
Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018; 20: 233–242.
Liu L, Feng D, Chen G, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. 2012; 14: 177–185.
Ney PA. Mitochondrial autophagy: origins, significance, and role of BNIP3 and NIX. Biochim Biophys Acta. 2015; 1853: 2775–2783.
Novak I, Kirkin V, McEwan DG, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010; 11: 45–51.
Sandoval H, Thiagarajan P, Dasgupta SK, et al. Essential role for nix in autophagic maturation of erythroid cells. Nature. 2008; 454: 232–235.
Schweers RL, Zhang J, Randall MS, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A. 2007; 104: 19500–19505.
Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015; 524: 309–314.
Narendra D, Tanaka A, Suen DF, et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008; 183: 795–803.
Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate parkin. PLoS Biol. 2010; 8: e1000298.
Kane LA, Lazarou M, Fogel AI, et al. PINK1 phosphorylates ubiquitin to activate parkin E3 ubiquitin ligase activity. J Cell Biol. 2014; 205: 143–153.
Kazlauskaite A, Kondapalli C, Gourlay R, et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014; 460: 127–139.
Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014; 510: 162–166.
Ordureau A, Sarraf SA, Duda DM, et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell. 2014; 56: 360–375.
Wei Y, Chiang WC, Sumpter RJr, et al. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell. 2017; 168: 224–238.e10.
Princely Abudu Y, Pankiv S, Mathai BJ, et al. NIPSNAP1 and NIPSNAP2 act as “eat me” signals for mitophagy. Dev Cell. 2019; 49: 509–525.e12.
Tanaka A, Cleland MM, Xu S, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by parkin. J Cell Biol. 2010; 191: 1367–1380.
Gelmetti V, De Rosa P, Torosantucci L, et al. PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation. Autophagy. 2017; 13: 654–669.
Sekine S, Youle RJ. PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol. 2018; 16: 2–017-0470-7.
Jin SM, Lazarou M, Wang C, et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol. 2010; 191: 933–942.
Jian F, Chen D, Chen L, et al. Sam50 regulates PINK1-parkin-mediated mitophagy by controlling PINK1 stability and mitochondrial morphology. Cell Rep. 2018; 23: 2989–3005.
Jin G, Xu C, Zhang X, et al. Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. Nat Immunol. 2018; 19: 29–40.
Lazarou M, Jin SM, Kane LA, et al. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase parkin. Dev Cell. 2012; 22: 320–333.
Okatsu K, Uno M, Koyano F, et al. A dimeric PINK1-containing complex on depolarized mitochondria stimulates parkin recruitment. J Biol Chem. 2013; 288: 36372–36384.
Sekine S, Wang C, Sideris DP, et al. Reciprocal roles of Tom7 and OMA1 during mitochondrial import and activation of PINK1. Mol Cell. 2019; 73: 1028–1043.e5.
Akabane S, Uno M, Tani N, et al. PKA regulates PINK1 stability and parkin recruitment to damaged mitochondria through phosphorylation of MIC60. Mol Cell. 2016; 62: 371–384.
Yan C, Gong L, Chen L, et al. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy. 2020; 16: 419–434.
Jin SM, Youle RJ. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy. 2013; 9: 1750–1757.
Antonioli M, Di Rienzo M, Piacentini M, et al. Emerging mechanisms in initiating and terminating autophagy. Trends Biochem Sci. 2017; 42: 28–41.
Van Humbeeck C, Cornelissen T, Hofkens H, et al. Parkin interacts with Ambra1 to induce mitophagy. J Neurosci. 2011; 31: 10249–10261.
Strappazzon F, Nazio F, Corrado M, et al. AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ. 2015; 22: 419–432.
Di Rita A, D’Acunzo P, Simula L, et al. AMBRA1-mediated mitophagy counteracts oxidative stress and apoptosis induced by neurotoxicity in human neuroblastoma SH-SY5Y cells. Front Cell Neurosci. 2018; 12: 92.
Di Rita A, Peschiaroli AD, Acunzo P, et al. HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha. Nat Commun. 2018; 9: 3755-018-05722-3.
Strappazzon F, Di Rita A, Peschiaroli A, et al. HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy. Cell Death Differ. 2020; 27: 1155–1168.
Miki Y, Tanji K, Mori F, et al. Alteration of upstream autophagy-related proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1) in Lewy body disease. Brain Pathol. 2016; 26: 359–370.
Li H, Ham A, Ma TC, et al. Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy. 2019; 15: 113–130.
Zhou J, Zhao Y, Li Z, et al. miR-103a-3p regulates mitophagy in Parkinson’s disease through Parkin/Ambra1 signaling. Pharmacol Res. 2020; 160: 105197.
Arena G, Gelmetti V, Torosantucci L, et al. PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating bcl-xL and impairing its pro-apoptotic cleavage. Cell Death Differ. 2013; 20: 920–930.
Gibellini L, De Gaetano A, Mandrioli M, et al. The biology of Lonp1: more than a mitochondrial protease. Int Rev Cell Mol Biol. 2020; 354: 1–61.
Quiros PM, Langer T, Lopez-Otin C. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol. 2015; 16: 345–359.
Thomas RE, Andrews LA, Burman JL, et al. PINK1-parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet. 2014; 10: e1004279.
Gilquin B, Taillebourg E, Cherradi N, et al. The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes. Mol Cell Biol. 2010; 30: 1984–1996.
Di Rienzo M, Antonioli M, Fusco C, et al. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Sci Adv. 2019; 5: eaau8857.
Silvestri L, Caputo V, Bellacchio E, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet. 2005; 14: 3477–3492.
Tyanova S, Temu T, Sinitcyn P, et al. The perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016; 13: 731–740.
Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019; 47: D607–D613.