Rheb Regulates Mitophagy Induced by Mitochondrial Energetic Status

Melser, Su; Chatelain, Étienne Hébert; Lavie, Julie; Mahfouf, Walid; Jose, Caroline; Obre, Émilie; Goorden, Susan; Priault, Muriel; Elgersma, Ype; Rezvani, Hamid Reza; Rossignol, Rodrigue; Bénard, Giovanni

doi:10.1016/j.cmet.2013.03.014

Cited by 221 publications

(183 citation statements)

References 47 publications

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“…Third, a defect in mitochondrial turnover could be perpetuated by increased metabolic flux. Previous studies have suggested that mitophagy is impaired in the diabetic kidney (57), and mitophagy is linked to mitochondrial bioenergetics (58,59).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Sas¹,

Kayampilly²,

Byun³

et al. 2016

JCI Insight

205

210

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Section: Discussionmentioning

confidence: 99%

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Sas¹,

Kayampilly²,

Byun³

et al. 2016

JCI Insight

205

210

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“…It has been reported that the stimulation of mitochondrial oxidative phosphorylation enhances mitochondrial renewal by increasing its degradation rate. 26 This indicates that mitochondrial homeostasis and oxidative phosphorylation could be mutually beneficial. Mitochondrial quality control may serve as an important mechanism maintaining cellular energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Chaperone-like protein p32 regulates ULK1 stability and autophagy

Jiao¹,

Gq²,

Dong³

et al. 2015

Cell Death Differ

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Mitophagy mediates clearance of dysfunctional mitochondria, and represents one type of mitochondrial quality control, which is essential for optimal mitochondrial bioenergetics. p32, a chaperone-like protein, is crucial for maintaining mitochondrial membrane potential and oxidative phosphorylation. However, the relationship between p32 and mitochondrial homeostasis has not been addressed. Here, we identified p32 as a key regulator of ULK1 stability by forming complex with ULK1. p32 depletion potentiated K48-linked but impaired K63-linked polyubiquitination of ULK1, leading to proteasome-mediated degradation of ULK1. As a result, silencing p32 profoundly impaired starvation-induced autophagic flux and the clearance of damaged mitochondria caused by mitochondrial uncoupler. Importantly, restoring ULK1 expression in p32-depleted cells rescued autophagy and mitophagy defects. Our findings highlight a cytoprotective role of p32 under starvation conditions by regulating ULK1 stability, and uncover a crucial role of the p32-ULK1-autophagy axis in coordinating stress response, cell survival and mitochondrial homeostasis. Mitophagy is a selective form of autophagy by which mitochondria are degraded in autolysosomes. p32 is a critical regulator of mitochondrial bioenergetics. 1 It primarily localizes to the mitochondrial matrix, but has also been reported to be present in other subcellular locations. 2-5 Many human tumors exhibit higher p32 expression levels than their nonmalignant counterpart tissues. 6-9 Depleting p32 in human cancer cells strongly shifts their metabolism from oxidative phosphorylation to glycolysis. 1 Consistently, p32 knockout causes mid-gestation lethality of knockout embryos and defects in oxidative phosphorylation. Mouse embryonic fibroblasts (MEFs) generated from p32 knockout embryos exhibited impaired ATP production and reduced mitochondrial membrane potential, which is in agreement with the observation that p32 silencing leads to increased mitochondrial fragmentation. 10,11 Notably, p32 was found to form protein complex with a variety of molecules 7,12,13 and has been suggested that it may act as a multifunctional chaperone protein. [12][13][14] ULK1 has a crucial role in mitophagy induction. 15 Despite the pivotal role of ULK1 in mitochondrial clearance, little is known as how ULK1 itself is regulated. ULK1 is a relatively stable protein and is subject to proteasome-mediated degradation. Post-translational modifications including K63-linked ubiquitylation 16,17 and phosphorylation [18][19][20] have been reported to modulate the rates of ULK1 turnover and kinase activity in different cellular contexts. Hsp90 and Cdc37 have been shown to regulate ULK1 stability and activity by forming complex with ULK1, which subsequently influences Atg13-mediated mitophagy. 21 Here, we found p32 regulates ULK1 stability by forming protein complex with ULK1. The interaction between ULK1 and p32 is crucial for maintaining the steady-state levels and activity of ULK1. We further show that p32 ablation results in a ...

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“…In this way BNIP3 may facilitate the excision of damaged mitochondrial from network and prevent re-fusion (Landes et al, 2010;Lee et al, 2011). Finally, under conditions stimulating high levels of oxidative phosphorylation, Rheb, a small GTPase, is recruited to mitochondria and interacts directly with NIX and LC3 (Melser et al, 2013). Overexpression of Rheb increases LC3 processing and induces mitophagy in a NIX-dependent manner, suggesting NIX has a fundamental role in Rheb recruitment under conditions of high oxidative stress where maintaining a health population of mitochondria is vital (Melser et al, 2013).…”

Section: Molecular Physiology Of Mitochondrial Quality Controlmentioning

confidence: 99%