PINK1-Phosphorylated Mitofusin 2 Is a Parkin Receptor for Culling Damaged Mitochondria

Chen, Yun; Dorn, Gerald W.

doi:10.1126/science.1231031

Cited by 1,118 publications

(1,083 citation statements)

References 24 publications

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“…MFN2 plays a central role in autophagy induction in the liver (Biel et al., 2016), skeletal and cardiac muscle (Chen & Dorn, 2013; Sebastián et al., 2012). Our findings here not only provide mechanistic correlation of SIRT1‐MFN2 axis in autophagy regulation in the liver but also explain why aged livers are intrinsically vulnerable to ischemic stress.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, pathologically low levels of MFN2 may adversely affect the delivery of autophagosomes to lysosomes, as MFN2 may be involved in the fusion between the autophagosome and the lysosome through its interaction with the Ras‐related protein Rab7 (Zhao et al., 2012). On the other hand, as MFN2 ubiquitination by PTEN‐induced kinase 1(PINK1) serves as a mitophagy signal for identifying and clearing damaged mitochondria (Chen & Dorn, 2013), depletion of MFN2 during I/R could prevent PINK1‐associated mitophagy in old livers. Noticeably, I/R also significantly decreased MFN1 expression in old hepatocytes (Figure S4A).…”

Section: Discussionmentioning

confidence: 99%

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Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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SummaryIschemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age‐mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near‐complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co‐overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C‐terminus of MFN2, leading to autophagy activation. The SIRT1‐MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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“…Loss of the mitochondrial membrane potential triggers PINK1 accumulation on the surface of mitochondria and phosphorylates mitochondrial outer membrane proteins 49, 53. This process accelerates Parkin translocation from the cytosol to the mitochondria,49, 54 and thus ubiquitinates mitochondrial outer membrane proteins to promote recruitment of an autophagosome 55. Other than the PINK1/Parkin pathway, BNIP3, BNIP3L and FUNDC1 are also emerging key players in the regulation of mitophagy 13, 56, 57.…”

Section: Discussionmentioning

confidence: 99%

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Wang

Zhao

Feng

et al. 2018

J Cellular Molecular Medi

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Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG‐treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up‐regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20‐like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin‐mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

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“…It has been reported that Pink1 phosphorylates Miro and participates in mitochondrial depolarization 23 . Pink1 phosphorylates Mfn2 and mediates mitochondrial degradation 24 . Pink1 binds and colocalizes with TRAP1 in the mitochondria.…”

Section: Pink1 Inhibits Mitochondrial Fragmentation and Apoptosismentioning

confidence: 99%

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Wang

Zhou

et al. 2015

Nat Commun

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Mitochondrial fragmentation plays an important role in the progression of cardiac diseases, such as myocardial infarction and heart failure. Mitochondrial network is controlled by many factors in different cell types. Here we show that the interplay between E2F1, miR-421 and Pink1 regulates mitochondrial morphology and cardiomyocyte cell death. Pink1 reduces mitochondrial fragmentation and protects cardiomyocyte from apoptosis. On the other hand, miR-421 promotes cardiomyocyte mitochondrial fragmentation, apoptosis and myocardial infarction by suppressing Pink1 translation. Finally, we show that transcription factor E2F1 activates miR-421 expression. Knocking down E2F1 suppresses mitochondrial fragmentation, apoptosis and myocardial infarction by affecting miR-421 levels. Collectively, these data identify the E2F1/miR-421/Pink axis as a regulator of mitochondrial fragmentation and cardiomyocyte apoptosis, and suggest potential therapeutic targets in treatment of cardiac diseases.

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PINK1-Phosphorylated Mitofusin 2 Is a Parkin Receptor for Culling Damaged Mitochondria

Cited by 1,118 publications

References 24 publications

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

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