Central Role of Mitofusin 2 in Autophagosome-Lysosome Fusion in Cardiomyocytes

Zhao, Ting; Huang, Xiaohu; Han, Liang; Wang, Xianhua; Cheng, Hongqiang; Zhao, Yungang; Chen, Quan; Chen, Ju; Cheng, Heping; Xiao, Rui‐Ping; Zheng, Ming

doi:10.1074/jbc.m112.379164

Cited by 184 publications

(174 citation statements)

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“…Therefore, the severe reduction of MFN2 expression during ischemia can alter the integrity of mitochondria‐ER interaction, thereby disrupting the platform for autophagosome or mitophagosome formation, although some reports do not support this tethering function of MFN2 (Cosson, Marchetti, Ravazzola & Orci, 2012; Filadi et al., 2015, 2017). 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.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, SIRT1 overexpression reversed pathological events through its interaction with and subsequent deacetylation of MFN2. This mitochondrial outer membrane protein has diverse functions such as mitochondrial fusion (Chen et al., 2003), tethering between mitochondria and endoplasmic reticulum (ER) (de Brito & Scorrano, 2008; Naon et al., 2016), metabolic regulation (Bach et al., 2003; Sebastián et al., 2012), and the endocytic/secretory pathway (Daniele et al., 2014; Zhao et al., 2012). It is currently unknown how SIRT1 and MFN2 are affected by I/R in old hepatocytes.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Increased autophagy defects, mitochondrial dysfunction, and cell death have been found in MFN2-null cardiomyocytes after I/R. 34 MFN2 KO animals are embryonically lethal, 35 whereas SIRT1 KO mice are born alive. Thus, it is plausible that MFN2-deficient cells may be more prone to I/R injury than SIRT1-null cells.…”

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confidence: 99%

Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner

et al. 2015

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Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. The role of Sirtuin 1 (SIRT1) in hepatic I/R injury remains elusive. Using human and mouse livers, we investigated the effects of I/R on hepatocellular SIRT1. SIRT1 expression was significantly decreased after I/R. Genetic overexpression or pharmacological activation of SIRT1 markedly suppressed defective autophagy, onset of the mitochondrial permeability transition, and hepatocyte death after I/R, whereas SIRT1-null hepatocytes exhibited increased sensitivity to I/R injury. Biochemical approaches revealed that SIRT1 interacts with mitofusin-2 (MFN2). Furthermore, MFN2, but not MFN1, was deacetylated by SIRT1. Moreover, SIRT1 overexpression substantially increased autophagy in wild-type cells, but not in MFN2-deficient cells. Thus, our results demonstrate that the loss of SIRT1 causes a sequential chain of defective autophagy, mitochondrial dysfunction, and hepatocyte death after I/R. Cell Death and Differentiation (2016) 23, 279-290; doi:10.1038/cdd.2015; published online 17 July 2015During hepatic resection and liver transplantation operations, inflow occlusion is employed to temporarily limit blood flow to minimize intraoperative blood loss. Although prolonged ischemia eventually causes tissue injury, severe damage paradoxically does not occur until recovery of blood flow and restitutions of normal physiological pH.1 Ischemia/reperfusion (I/R) injury is a key cause of postoperative liver failure during hemorrhagic shock, hepatectomy, and liver transplantation. Despite continuous efforts, substantial benefits from current strategies have not been realized, mainly because of the multifactorial nature of I/R injury.I/R initiates opening of high-conductance permeability transition pores in the mitochondrial inner membranes, leading to mitochondrial permeability transition (MPT).2 Onset of the MPT uncouples oxidative phosphorylation and depolarizes mitochondrial membrane potential (ΔΨ m ) that in turn causes ATP depletion and cell death.Autophagy is an evolutionarily conserved catabolic process. Among the three forms of autophagy, macroautophagy is of particular importance in the liver, as it not only degrades unneeded intracellular proteins but also digests injured or dysfunctional organelles such as abnormal mitochondria. 3 We have shown that impaired autophagy contributes to liver I/R injury. [4][5][6] Sirtuin1 (SIRT1) deacetylates Lys residues of both histone and nonhistone targets, and is activated in response to fasting and calorie restriction in the liver, a condition inducing autophagy. 7,8 Despite its extramitochondrial localization, SIRT1 appears to affect mitochondrial biogenesis 9 and bioenergetics, 10 but its mechanisms remain elusive. Using isolated hepatocytes, mouse livers, SIRT1-null mice, and human livers, we here demonstrate that I/R depletes livers of SIRT1 and that specific overexpression of SIRT1 mitigates defective autophagy, onset of the MPT, and subsequent hepatocyte death after both in vitro...

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“…Ubiquitination of mitofusin 2 (Mfn2) prevents fusion with the remainder of the mitochondrial network [2], and participation of Drp1 and Mfn2 in mitophagy has been established [3,4]. Nix and Bnip3 have been shown to stimulate mitophagy, likely through triggering depolarization and subsequent Parkin recruitment [5].…”

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confidence: 99%

Indigestible mitochondria cause heartburn

Gottlieb

Linton

2012

Cell Res

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The link between impaired autophagic flux (autophagus interruptus), damaged mitochondria, and myocardial inflammation has been further tightened with the recent paper by Oka and colleagues, in which failure to degrade mitochondrial DNA exacerbated myocardial inflammation in the context of pressure overload. Using mice with cardiac-specific deletion of the lysosomal DNase II that were subjected to aortic banding, Otsu's group showed that mitochondrial DNA accumulated in lysosomes and resulted in TLR9-dependent production of inflammatory cytokines.The link between autophagy, mitochondria, and inflammation in the heart has been further tightened with the recent paper in Nature by Oka et al [1]. In this work, Otsu's team showed that mitochondrial DNA (mtDNA) that escapes autophagy led to the activation of TLR9 and inflammation. Mice with cardiac-specific deletion of lysosomal DNase II (DNase2a -/-) developed accelerated myocarditis and heart failure after the induction of pressure overload with thoracic transverse aortic constriction (TAC). Cardiomyocytes in TAC-treated DNase2a -/-mice showed increased expression of IL-1β and IL-6, which was followed by infiltration of CD68 + macrophages and Ly6G + cells.

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Central Role of Mitofusin 2 in Autophagosome-Lysosome Fusion in Cardiomyocytes

Cited by 184 publications

References 60 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

Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner

Indigestible mitochondria cause heartburn

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