Molecular mechanisms and physiological functions of mitophagy

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(3)

Published: Jan. 13, 2021

Review13 January 2021Open Access Molecular mechanisms and physiological functions of mitophagy Mashun Onishi orcid.org/0000-0003-1511-4097 Laboratory Mitochondrial Dynamics, Graduate School Frontier Biosciences, Osaka University, Suita, JapanThese authors contributed equally to this work Search for more papers by author Koji Yamano orcid.org/0000-0002-4692-161X The Ubiquitin Project, Tokyo Metropolitan Institute Medical Science, Tokyo, Miyuki Sato Corresponding Author [email protected] orcid.org/0000-0002-1944-4918 Membrane Biology, Cellular Regulation, Gunma Maebashi, Japan Noriyuki Matsuda orcid.org/0000-0001-8199-952X Okamoto orcid.org/0000-0003-4730-4522 Information Onishi1, Yamano2, *,3, *,2 *,1 1Laboratory 2The 3Laboratory *Corresponding author. Tel: +81 27 220 8842; E-mail: 3 5316 3244; 6 6879 7970; EMBO Journal (2021)40:e104705https://doi.org/10.15252/embj.2020104705 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Degradation mitochondria via a selective form autophagy, named mitophagy, is fundamental mechanism conserved from yeast humans that regulates mitochondrial quality quantity control. Mitophagy promoted specific outer membrane receptors, or ubiquitin molecules conjugated proteins on surface leading formation autophagosomes surrounding mitochondria. Mitophagy-mediated elimination plays an important role many processes including early embryonic development, cell differentiation, inflammation, apoptosis. Recent advances analyzing vivo also reveal high rates steady-state turnover diverse types, highlighting intracellular housekeeping mitophagy. Defects are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, aging, further underscoring biological relevance. Here, we review our current molecular understanding its implications, discuss how multiple pathways coordinately modulate fitness populations. ALLO-1 Allophagy-1 ATG Autophagy-related protein BCL2L1/BCL-XL BCL2 like 1 BCL2L13 B-cell lymphoma 2-like 13 BNIP3 adenovirus E1B 19-kDa-interacting BNIP3L Nip3-like X (NIX)/BNIP3-like CCCP Carbonyl cyanide m-chlorophenylhydrazone cGAS Cyclic GMP-AMP synthase CK2 Casein kinase 2 CPS-6 endonuclease G DFCP1/ZFYVE1 DFCP1/zinc finger FYVE-type containing FIP200/RB1CC1 FIP200/RB1-inducible coiled-coil Fis1 Fission, FKBP8/FKBP38 FK506-binding 8 FOXO1 Forkhead box O1 FUNDC1 FUN14 domain-containing GABARAP GABA type A receptor-associated GABARAPL1/2 protein-like 1/2 GFP Green fluorescent HOPS Homotypic fusion vacuole sorting IGF-1 Insulin-like growth factor Keap1 Kelch-like ECH-associated LC3A/B/C Microtubule-associated light chain alpha/beta/gamma LIR LC3-interacting region MARCH5/MITOL Membrane-associated ring-CH-type 5 MBP Maltose-binding Miro Rho mTORC1 Mechanistic target rapamycin complex MUL1 E3 ligase NBR1 autophagy cargo receptor NDP52/CALCOCO2 NDP52/calcium binding domain NLRP3 NLR family pyrin NOD Nucleotide-binding oligomerization NRF2 Nuclear factor, erythroid OPTN Optineurin p62/SQSTM1 p62/Sequestosome PARL Presenilin-associated rhomboid-like PC Phosphatidylcholine PE Phosphatidylethanolamine PGAM5 PGAM member 5, serine/threonine phosphatase PI Phosphatidylinositol PI3K 3-kinase PI3P Phosphatidylinositol-3-phosphate PINK1 PTEN induced PLEKHM1 Pleckstrin homology RUN M1 RABGEF1 RAB guanine nucleotide exchange Rheb Ras homolog, SNARE Soluble N-ethylmaleimide-sensitive attachment Src SRC proto-oncogene, non-receptor tyrosine STING Stimulator interferon genes TAX1BP1 Tax1 TBC1D15 TBC1 15 TBC1D17 17 TBK1 TANK-binding TOMM/TOM Translocase TORC1 Target UBAN Ubiquitin-binding ABIN NEMO ULK1 Unc-51-like activating USP protease VDAC Voltage-dependent anion channel VPS Vacuolar WIPI WD repeat domain, phosphoinositide interacting Introduction Mitochondria double-membrane-bound subcellular compartments function ATP production, phospholipid biosynthesis/transport, calcium signaling, iron homeostasis (Raffaello et al, 2016; Tamura Endo, 2017; Spinelli Haigis, 2018). These organelles act platforms events apoptosis, innate immune response, differentiation (Mehta Kalkavan Green, 2018; Lisowski Since generate reactive oxygen species (ROS) electron transport chain, they constantly challenged oxidative stress ultimately may lead their structural functional failure (Wong 2017). Therefore, cells need sophisticated systems maintaining fitness. control relies pathways: ROS scavenging, DNA repair, refolding/degradation (Scheibye-Knudsen 2015). In addition these processes, fission play key roles (Eisner While promotes content mixing between healthy partially dysfunctional mitochondria, separates damaged components pool. autophagic system targets impaired delivers them lysosomes degradation. This catabolic process, called contributes (Pickles 2018) types. tissues consuming large amount brain, skeletal muscle, heart, liver, kidney, highly developed order maintain proper balance energy demand supply. When shifted normoxia hypoxia, decrease quantity, thereby adapting cellular metabolism anaerobic (Wu Chen, Thus, biogenesis degradation two opposing determine (Ploumi addition, almost completely eliminated during erythrocyte maturation (Ney, Furthermore, accumulating evidence reveals maternal inheritance (mtDNA) depends clearance sperm-derived paternal embryogenesis (Sato Sato, Although generally recognized bulk process non-selectively transports cytoplasmic nucleic acids, proteins, (Nakatogawa, 2020), it acts mediate particular (Gatica one organelle-specific serves structure (Okamoto, 2014) (Fig 1). term "mitophagy" was first coined 2005 (Lemasters, 2005; Priault 2005), within few years, major breakthroughs led discovery selectively (Okamoto 2009; Kanki 2009b) mammalian (Schweers 2007; Narendra 2008; Sandoval 2008). review, will describe underlying yeast, worms, Drosophila, cover pathophysiological functions. Figure 1. Overview (1) Intra- extracellular cues promote isolation excess fragmentation tubular networks. (2) receptors ubiquitin–autophagy adaptors confer selectivity recruited and/or activated (3) Core autophagy-related membrane/phagophore (4) Targeted enclosed sequestrated autophagosomes. (5) Autophagosomes transported fused lytic vacuoles mammals. (6) Lysosomal vacuolar acidic hydrolases flow into degrade contents be recycled. Download figure PowerPoint Receptor-mediated Regulation Atg32 budding Saccharomyces cerevisiae mostly mediated Atg32, single-pass transmembrane (OMM) 2009) 2A). unicellular eukaryote, when grown stationary phase upon nitrogen starvation (Tal Klionsky, 2009). Under conditions, expression at transcriptional level accumulates OMM, forming Atg8 Atg11 localized autophagosomes, scaffold other Atg autophagosome formation. Loss abolishes while overexpression increases activity, suggesting molecule rate-limiting regulating number degraded. specifically dispensable types cytoplasm-to-vacuole targeting pathway, ER-phagy, pexophagy. 2. (A) Schematic representation structures AIM/LIR, Atg8-family protein-interacting motif/LC3-interacting (pink); TM, (light blue); BH1-4, Bcl-2 1-4 (green green); PPlase, peptidyl-prolyl cis-trans isomerase (orange); TPR, tetratricopeptide (purple); CaM, calmodulin-binding (dark red). size indicated amino acids. (B-D) Models activation recruitment surface. (B), BNIP3, BCL2L13, FKBP8 (C), FUNDC1, NIX (D) bind ATG8 then machinery Phosphorylation dephosphorylation serve regulatory activity receptors. For details, see text. Several lines phosphorylation event Atg32-mediated 2B). During respiration shift starvation, phosphorylated manner dependent Atg11-interacting motif Ser114 Ser119 (Aoki 2011; Kondo-Okamoto 2012). Importantly, post-translational modification CK2, evolutionarily variety (Kanki 2013). interacts directly phosphorylates vitro Mutagenesis Ser114, Ser119, residues impairment destabilizes Atg32-Atg11 interactions strongly suppresses 2012; 2013), CK2-dependent could step activate recruiting recent study has demonstrated 2A (PP2A)-like Ppg1 critical negatively (Furukawa lacking Ppg1, even respiratory log (stage prior induction), likely resulting increased accelerate Ppg1-dependent suppression requires partners Far have previously been suggested pheromone-induced cycle arrest (Pracheil Liu, findings raise possibility Ppg1-Far dephosphorylates competing against CK2-mediated under non-inducing conditions. known proteolytically cleaved Yme1, catalytic subunit metalloprotease inner (IMM) belongs ATPases activities (AAA) (Leonhard 1996). Upon processed C-terminal portion Yme1-dependent (Wang 2013) Yme1 leads strong support idea Yme1-mediated proteolysis required efficient However, studies suggest minor no deficiencies (Welter 2013; Gaspard McMaster, 2015), raising processing relevant some strains ER factors connected contact sites ER–mitochondria encounter (ERMES) facilitates transfer (Kornmann ERMES discrete foci where closely positioned, loss severe defects starvation-induced (Bockler Westermann, 2014). component Mmm1 forms co-localize dot-like structures, Ubiquitylation Mdm12/34 Rsp5 linked (Belgareh-Touze regulated Get1/2 Opi3, (Sakakibara 2015; insertion tail-anchored (Schuldiner Schuldiner Wang causes slightly hardly affected (Onishi How trans remains unclear. Surprisingly, methyltransferase ER, induction Opi3 biosynthesis pathway conversion PC. Depletion aberrant elevation glutathione levels reduces thus affects (Deffieu Sakakibara respiring coordinate methylation through unknown mechanisms. mammals mammals, mechanistically than different signals developmental changes. Disruption potential potent trigger (Elmore 2001). CCCP, proton-selective ionophore, antimycin (an inhibitor III) commonly impair Because toxic induces non-physiological damage especially neurons, often induce neuronal (Cai Ashrafi Both reagents depolarization accumulation OMM. integral members (LC3A/B/C, GABARAP, GABARAP-L1/2) regions (LIRs) regulate membranes enclosing Two One group includes (also NIX) (Boyd 1994; Matsushima 1998; Chen 1999; Vande Velde 2000; Regula 2002; Kubli Schweers Hanna 2012), (Liu counterpart (Murakawa 2015) following part, namely FKBP (Bhujabal hypoxic (Zhang response upregulated anchored OMM (TM) exposing N-terminal cytosol (Hanna usually expressed inactive monomer cytosol, but signals, stable homodimer TM integrated (Chen 1997; Ray mutations, which disrupt homodimerization do not affect localization, cause defect, supporting Similar 2A) mutations block interaction LC3, defects. Ser17 Ser24 near BNIP3-LC3 (Zhu 2C). shows (53–56% acid sequence identity) (Matsushima 1999) reticulocyte nucleus, eliminated, so erythrocytes can keep maximum space hemoglobin (Koury Yoshida Fader Colombo, 2006). With similarity restore reticulocytes contains LC3A, LC3B, GABARAP-L1, GABARAP-L2 (Novak 2010) CCCP-treated cells, recruits GABARAP-L1 2010). Ser34 Ser35, tandem serine motif, stabilizes NIX-LC3 (Rogov 2017) 2D). dimerization NIX, region, (Marinkovic 2020). Accumulation (triggered phosphorylation) NIX-mediated LC3 (Melser phosphorylation, Rheb, small GTPase superfamily, translocates mitophagosome Expression HeLa respiration, decreases consumption capacity Whether phenotypes depend Rheb-induced addressed. shown inhibit crucial (Li 2007). As (Bartolome 2017), BNIP3-dependent inhibition might facilitate take part positive feedback loop amplify initiation signal reported PINK1/Parkin-mediated ubiquitylated Parkin, turn adaptor binds both LC3/GABARAP (Gao Parkin translocation 2016a). CCCP-induced depolarization, (Ding 2010b). Pathophysiological relevance Parkinson's disease unknown. hypoxia-induced It typical three domains 2012) Mutations FUNDC1-LC3 OMM-anchored ubiquitylate several acting dynamics (Yonashiro 2006; Sugiura Park decreased hypoxia ubiquitin–proteasome-dependent due MARCH5-mediated ubiquitylation Lys119 Knockdown endogenous MARCH5 mutant impairs enhancing Ser13 Tyr18 located motif. mediates becomes inactivated, causing Tyr18, stabilization promotion enhances Hypoxia (near motif) 2014b). variant defective inhibits normoxic BCL2L1/Bcl-xL, antiapoptotic BH3 molecule, PGAM5-FUNDC1 prevent 2014a). homologs far identified motifs morphology fragmentation, silencing elongation BCL2L13-dependent conventional Atg7, core essential lipidation second reduce absence notion seems contribute regulation BCL2L13-LC3 mutation Ser272 localize 2019). elucidated. immunosuppressant drug FK506 tacrolimus) transcription, folding/trafficking, apoptosis (Bonner Boulianne, Co-overexpression LC3A depolarized CCCP-treated, Parkin-depleted canonical N-terminus C-terminus preferentially over vivo, Moreover, escape degradation-prone localizes (Saita Bhujabal Given complexity versatile needed clarify whether involved Ubiquitin-mediated (PD) neurodegenerative characterized death dopaminergic neurons (Lotharius Brundin, 2002). PD occurs sporadically 1–2% people above 65 years age arise earlier genetic mutations. Common observed patients motor symptoms (tremor, bradykinesia, rigidity, postural instability) result substantia nigra. Non-motor autono

Language: Английский

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Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

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Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation

Theranostics, Journal Year: 2023, Volume and Issue: 13(2), P. 736 - 766

Published: Jan. 1, 2023

Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining intracellular homeostasis.In recent years, has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such neurodegenerative cardiovascular cancer, metabolic so on.It been found regulation may become new direction for treatment some diseases.In addition, numerous small molecule modulators have also reported, which provides opportunities comprehend procedure potential therapeutic development.Taken together, in this review, we summarize current understanding mechanism mitophagy, discuss roles its relationship with introduce existing small-molecule pharmacological further highlight significance their development.

Language: Английский

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Mechanisms of Selective Autophagy

Annual Review of Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 37(1), P. 143 - 169

Published: June 21, 2021

Selective autophagy is the lysosomal degradation of specific intracellular components sequestered into autophagosomes, late endosomes, or lysosomes through activity selective receptors (SARs). SARs interact with autophagy-related (ATG)8 family proteins via sequence motifs called LC3-interacting region (LIR) in vertebrates and Atg8-interacting (AIMs) yeast plants. can be divided two broad groups: soluble membrane bound. Cargo substrate selection may independent dependent ubiquitin labeling cargo. In this review, we discuss mechanisms mammalian a focus on unifying principles employed recognition, interaction forming autophagosome LIR-ATG8 interactions, recruitment core for efficient formation substrate.

Language: Английский

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The mitophagy pathway and its implications in human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 16, 2023

Abstract Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, crucial for metabolism survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria maintain mitochondrial fine-tuning numbers balance intracellular homeostasis. Growing evidences show that mitophagy, an acute tissue stress response, plays important role maintaining the health of network. Since timely removal abnormal is essential survival, cells have evolved variety mitophagy pathways ensure can be activated time under various environments. A better understanding diseases treatment therapeutic target design. In this review, we summarize molecular mechanisms mitophagy-mediated elimination, how maintains homeostasis at system levels organ, what alterations related development diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., recent advances. Finally, potential clinical applications outline conditions regulators enter trials. Research advances signaling transduction will developing new strategies precision medicine.

Language: Английский

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The landscape of aging

Science China Life Sciences, Journal Year: 2022, Volume and Issue: 65(12), P. 2354 - 2454

Published: Sept. 2, 2022

Language: Английский

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Biomarkers of aging

Science China Life Sciences, Journal Year: 2023, Volume and Issue: 66(5), P. 893 - 1066

Published: April 11, 2023

Language: Английский

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Autophagy and the hallmarks of aging

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101468 - 101468

Published: Sept. 24, 2021

Language: Английский

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ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 23

Published: Oct. 19, 2022

Reactive oxygen species (ROS) are bioproducts of cellular metabolism. There is a range molecules with oxidizing properties known as ROS. Despite those being implied negatively in aging and numerous diseases, their key role signaling evident. ROS control several biological processes such inflammation, proliferation, cell death. The redox underlying these events one characteristic the new generation scientists aimed at defining environment. potential, which includes balance sources antioxidant system, implies an important target for understanding cells’ fate derived from signaling. In this review, we summarized chemical, balance, signaling, implications aging.

Language: Английский

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PINK1/Parkin-mediated mitophagy in neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 84, P. 101817 - 101817

Published: Dec. 9, 2022

Language: Английский

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