Regulation of PINK1-Parkin-mediated mitophagy

Springer, Wolfdieter; Kahle, Philipp J.

doi:10.4161/auto.7.3.14348

Cited by 158 publications

(120 citation statements)

References 137 publications

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“…Recent work in a variety of systems showed that a PINK1/ Parkin pathway eliminates defective mitochondria by an autophagy mechanism (1,2,14). Our data support a model in which VDACs are part of this mechanism by recruiting Parkin to defective mitochondria.…”

Section: Discussionsupporting

confidence: 75%

“…Upon targeting to mitochondria, Parkin is activated and ubiquitinates mitochondrial proteins (6,7,32). Parkin variants that lack ubiquitin ligase activity can be recruited to mitochondria but are unable to promote mitophagy, suggesting that ubiquitination of mitochondrial proteins by Parkin is essential for mitophagy but not for its recruitment to mitochondria (2). Several mitochondrial ubiquitination targets of Parkin have been identified in mammalian systems and in flies.…”

mentioning

confidence: 99%

“…The serine/threonine kinase PINK1 and the RING family ubiquitin ligase Parkin were recently found to be involved in the elimination of defective mitochondria by mitochondrial autophagy (mitophagy) (1,2). Mitophagy is thought to protect cells from the deleterious effects of accumulating functionally deficient mitochondria and increased production of reactive oxygen species (3,4).…”

mentioning

confidence: 99%

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Voltage-dependent Anion Channels (VDACs) Recruit Parkin to Defective Mitochondria to Promote Mitochondrial Autophagy

Sun

Vashisht

Tchieu

et al. 2012

Journal of Biological Chemistry

189

150

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Background: Parkin is recruited to defective mitochondria to promote degradation by an autophagy mechanism (mitophagy). Results: VDACs specifically interact with Parkin on defective mitochondria and are required for efficient targeting of Parkin to mitochondria and subsequent mitophagy. Conclusion: VDACs recruit Parkin to defective mitochondria. Significance: A novel mechanistic aspect of Parkin-dependent mitophagy is proposed that may be relevant to Parkinson disease.

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Voltage-dependent Anion Channels (VDACs) Recruit Parkin to Defective Mitochondria to Promote Mitochondrial Autophagy

Sun

Vashisht

Tchieu

et al. 2012

Journal of Biological Chemistry

189

150

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“…Figure 3a clearly indicates a drastic increase of the enzyme's transamidating activity on mitochondria that is evident after 18 h of CCCP treatment, in coincidence with the onset of mitophagy. 30 In line with this finding, it has been shown that the mitophagy onset is paralleled by the release of free calcium from the endoplasmic reticulum that is essential for TG2 activation. 31,32 It is important to note that the enzyme's activation on mitochondria is organelle specific as the same analysis carried out on the cytosolic fraction shows a very limited transamidating activity (Supplementary Figure S4A).…”

Section: Resultsmentioning

confidence: 65%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.

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“…Several studies in neuronal cells have shown that perinuclear clustering of mitochondria is initiated when mitochondria are damaged by various cellular stimuli, and is a prerequisite for the specific removal of impaired mitochondria through mitophagy. 1,36 In neuronal cells, SQSTM1 is required for ubiquitination-dependent clustering of damaged mitochondria caused by treatment with a mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone. 6,18,37 Thus, we hypothesized that SESN2 may induce perinuclear clustering of mitochondria by mediating the aggregation of SQSTM1 via SESN2-SQSTM1 interaction and by linking SQSTM1 to ubiquitins on the surface of damaged mitochondria.…”

Section: Sesn2 Induces Mitochondrial Priming By Facilitating Perinuclmentioning

confidence: 99%

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

et al. 2016

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Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

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Regulation of PINK1-Parkin-mediated mitophagy

Cited by 158 publications

References 137 publications

Voltage-dependent Anion Channels (VDACs) Recruit Parkin to Defective Mitochondria to Promote Mitochondrial Autophagy

Voltage-dependent Anion Channels (VDACs) Recruit Parkin to Defective Mitochondria to Promote Mitochondrial Autophagy

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

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