Endosomal Rab cycles regulate Parkin-mediated mitophagy

Yamano, Koji; Wang, Chunxin; Sarraf, Shireen A.; Münch, Christian; Kikuchi, Reika; Noda, Nobuo N.; Hizukuri, Yohei; Kanemaki, Masato T.; Harper, Wade; Tanaka, Keiji; Matsuda, Noriyuki; Youle, Richard J.

doi:10.7554/elife.31326

Cited by 135 publications

(128 citation statements)

References 65 publications

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“…ing C-I30 mRNP to OMM, cotranslational quality control factors and autophagy receptors to OMM-associated mRNPs, to the subsequent activation of mitophagy, could occur in the absence of Parkin. This contrasts the prevailing view that the activation of Parkin and subsequent ubiquitination of a battery of Parkin substrates on MOM is essential for PINK1-activated mitophagy 120. Consistent with previous studies, our results indicated that though not required, the presence of Parkin provides an amplifying mechanism to promote PINK1-directed mitophagy, as both the recruitment of autophagy receptors and the clearance of damaged mitochondria are accelerated in the presence of Parkin.…”

supporting

confidence: 84%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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supporting

confidence: 84%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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“…Another interesting candidate to relay the depolarization signal might be the protein kinase PINK1, which is stabilized on the outer mitochondrial membrane (OMM) of depolarized mitochondria (Narendra et al, 2010). An important role of PINK1 is to initiate PARKIN-mediated mitophagy by phosphorylating both PARKIN and ubiquitin (Okatsu et al, 2013;Pickles et al, 2018;Yamano et al, 2018). PINK1 is expressed in U2OS cells (McLelland et al, 2018) while PARKIN has not been detected (Durcan et al, 2014), so it is possible that stabilized PINK1 phosphorylates other substrates that control Arp2/3 complex activation.…”

Section: Discussionmentioning

confidence: 99%

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Fung

Higgs

et al. 2019

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statement: Mitochondrial depolarization induces Arp2/3 complex-dependent actin clouds that restrain mitochondrial shape changes induced by Oma1 on the inner mitochondrial membrane. A distinct actin network stimulates mitochondrial fission in response to calcium. Fung et al Actin and Mitochondria 2 AbstractRecent studies show that mitochondria and actin filaments work together in two contexts: 1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission, and 2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (<10 min). Calcium-induced actin assembly is INF2-dependent and Arp2/3 complex-independent, whereas depolarization-induced actin assembly is Arp2/3 complexdependent and INF2-independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as "clouds" around depolarized mitochondria. We have previously shown that calciuminduced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1. In contrast, depolarization-induced actin is temporally-associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent upon the protease Oma1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics. Fung et alActin and Mitochondria

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“…Mitofusin2 (MFN2), which is degraded by the proteasome following mitochondrial depolarization [22], underwent rapid degradation within 3 h of valinomycin treatment ( Fig 2D and E), in particular the mitochondria-rich fractions. MTCO2, an inner mitochondrial protein that is degraded via mitophagy following mitochondrial depolarization [40], was significantly decreased following 24 h of valinomycin treatment ( Fig 2D and E). In contrast, 3Flag-MITOL persisted throughout the first 6 h and only underwent a slight reduction after 24 h, confirming that the total cellular amount of MITOL is not dramatically decreased.…”

Section: Mitol Redistributes To Peroxisomes In Response To Mitochondrmentioning

confidence: 96%

Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes

et al. 2019

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Ubiquitylation of outer mitochondrial membrane (OMM) proteins is closely related to the onset of familial Parkinson's disease. Typically, a reduction in the mitochondrial membrane potential results in Parkin‐mediated ubiquitylation of OMM proteins, which are then targeted for proteasomal and mitophagic degradation. The role of ubiquitylation of OMM proteins with non‐degradative fates, however, remains poorly understood. In this study, we find that the mitochondrial E3 ubiquitin ligase MITOL/March5 translocates from depolarized mitochondria to peroxisomes following mitophagy stimulation. This unusual redistribution is mediated by peroxins (peroxisomal biogenesis factors) Pex3/16 and requires the E3 ligase activity of Parkin, which ubiquitylates K268 in the MITOL C‐terminus, essential for p97/VCP‐dependent mitochondrial extraction of MITOL. These findings imply that ubiquitylation directs peroxisomal translocation of MITOL upon mitophagy stimulation and reveal a novel role for ubiquitin as a sorting signal that allows certain specialized proteins to escape from damaged mitochondria.

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Endosomal Rab cycles regulate Parkin-mediated mitophagy

Cited by 135 publications

References 65 publications

Mechanisms and roles of mitophagy in neurodegenerative diseases

Mechanisms and roles of mitophagy in neurodegenerative diseases

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes

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