Regulation of mitophagy by the Gp78 E3 ubiquitin ligase

Fu, Min; St-Pierre, Pascal; Shankar, Jata; Wang, Peter T. C.; Joshi, Bharat; Nabi, Ivan R.

doi:10.1091/mbc.e12-08-0607

Cited by 173 publications

(173 citation statements)

References 46 publications

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“…S1A; see also Movies 1 and 2). The altered mitochondrial distribution in MGRN1-depleted cells was very similar to that observed in cells overexpressing GP78 (Fu et al, 2013) (Fig. S1B,C).…”

Section: Depletion Of Mgrn1 Results In Altered Mitochondrial Distribusupporting

confidence: 74%

“…Overexpression of functional GP78, but not its catalytic RING domain mutant, causes perinuclear mitochondrial clustering. This leads to increased ubiquitylation and degradation of mitofusins along with an increase in recruitment of LC3 (MAP1LC3A) to the mitochondria-associated ER (Fu et al, 2013). Degradation of mitofusins by GP78 is depolarization dependent, as this occurs in the presence of carbonyl cyanide m-chloro phenyl hydrazone (CCCP), thus suggesting a role for GP78 in quality control of depolarized mitochondria.…”

Section: Introductionmentioning

confidence: 99%

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Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

Mukherjee

Chakrabarti

2016

Journal of Cell Science

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Cellular quality control provides an efficient surveillance system to regulate mitochondrial turnover. This study elucidates a new interaction between the cytosolic E3 ligase mahogunin RING finger 1 (MGRN1) and the endoplasmic reticulum (ER) ubiquitin E3 ligase GP78 (also known as AMFR). Loss of Mgrn1 function has been implicated in late-onset spongiform neurodegeneration and congenital heart defects, among several developmental defects. Here, we show that MGRN1 ubiquitylates GP78 in trans through noncanonical K11 linkages. This helps maintain constitutively low levels of GP78 in healthy cells, in turn downregulating mitophagy. GP78, however, does not regulate MGRN1. When mitochondria are stressed, cytosolic Ca 2+ increases. This leads to a reduced interaction between MGRN1 and GP78 and its compromised ubiquitylation. Chelating Ca 2+ restores association between the two ligases and the in trans ubiquitylation. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy. This is important because functional depletion of MGRN1 by the membrane-associated disease-causing prion protein Ctm PrP affects polyubiquitylation and degradation of GP78, also leading to an increase in mitophagy events. This suggests that MGRN1 participates in mitochondrial quality control and could contribute to neurodegeneration in a subset of Ctm PrP-mediated prion diseases.

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“…S1A; see also Movies 1 and 2). The altered mitochondrial distribution in MGRN1-depleted cells was very similar to that observed in cells overexpressing GP78 (Fu et al, 2013) (Fig. S1B,C).…”

Section: Depletion Of Mgrn1 Results In Altered Mitochondrial Distribusupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

Mukherjee

Chakrabarti

2016

Journal of Cell Science

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“…Thus, the physiological role of Parkin-mediated mitophagy in mitochondrial homeostasis is not fully understood 14,29,30 . Indeed, mitophagy can occur in a PINK-Parkin cascade-independent manner [31][32][33][34][35] , although the mechanisms of Parkin-independent mitochondrial surveillance remain to be elucidated.…”

mentioning

confidence: 99%

Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance

et al. 2015

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AMP-activated protein kinase (AMPK) plays a central role in cellular energy sensing and bioenergetics. However, the role of AMPK in surveillance of mitochondrial damage and induction of mitophagy remains unclear. We demonstrate herein that AMPK is required for efficient mitophagy. Mitochondrial damage induces a physical association of AMPK with ATG16-ATG5-12 and an AMPK-dependent recruitment of the VPS34 and ATG16 complexes with the mitochondria. Targeting AMPK to the mitochondria is both sufficient to induce mitophagy and to promote cell survival. Recruitment of AMPK to the mitochondria requires N-myristoylation of AMPKb by the type-I N-myristoyltransferase 1 (NMT1). Our data support a spatiotemporal model wherein recruitment of AMPK in association with components of the VPS34 and ATG16 complex to damaged mitochondria regulates selective mitophagy to maintain cancer cell viability.

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“…Although E3 ligases often interact with substrates in a redundant manner, they can also impact protein folding and transcription independent of their ubiquitinating activities and can participate in the autophagydependent clearance of damaged mitochondria (mitophagy) (11,24,27).…”

mentioning

confidence: 99%

CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling

Palubinsky

Stankowski

Kale

et al. 2015

Antioxidants & Redox Signaling

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Aims: Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation. Results: We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTENinducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals. Utilizing a novel biotin-avidin capture technique, we found that the oxidation status of Parkin and the mitochondrial fission protein, dynamin-related protein 1 (Drp1), are altered in a CHIP-dependent manner. We also found that following oxygen-glucose deprivation (OGD), the expression of CHIP, PINK1, and the autophagic marker, LC3, increase and there is activation of the redox-sensitive kinase p66shc . Under conditions of OGD, CHIP relocalizes from the cytosol to mitochondria. Mitochondria from CHIP KO mice have profound impairments in stress response induced by calcium overload, resulting in accelerated permeability transition activity. While CHIP-deficient neurons are morphologically intact, they are more susceptible to OGD consistent with a previously unknown neuroprotective role for CHIP in maintaining mitochondrial homeostasis. Innovation: CHIP relocalization to the mitochondria is essential for the regulation of mitochondrial integrity and neuronal survival following OGD. Conclusions: CHIP is an essential regulator of neuronal bioenergetics and redox tone. Altering the expression of this protein has profound effects on neuronal survival when cells are exposed to OGD. Antioxid. Redox Signal. 23, 535-549.

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Regulation of mitophagy by the Gp78 E3 ubiquitin ligase

Cited by 173 publications

References 46 publications

Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

Ubiquitin mediated regulation of the E3 ligase GP78 by Mahogunin in trans affects mitochondrial homeostasis

Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance

CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling

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