The Experts below are selected from a list of 10062 Experts worldwide ranked by ideXlab platform
Quan Chen - One of the best experts on this subject based on the ideXlab platform.
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Mitophagy in cardiomyocytes and in platelets a major mechanism of cardioprotection against ischemia reperfusion injury
Physiology, 2018Co-Authors: Weilin Zhang, Lei Liu, Chuyan Chen, Jing Wang, Quan ChenAbstract:Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of Mitophagy and highlight the role of Mitophagy in cardioprotection.
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Mitophagy receptor fundc1 regulates mitochondrial homeostasis and protects the heart from i r injury
Autophagy, 2017Co-Authors: Weilin Zhang, Sami Siraj, Rong Zhang, Quan ChenAbstract:ABSTRACTMitophagy plays pivotal roles in the selective disposal of unwanted mitochondria, and accumulation of damaged mitochondria has been linked to aging-related diseases. However, definitive proof that Mitophagy regulates mitochondrial quality in vivo is lacking. It is also largely unclear whether damaged mitochondria are the cause or just the consequence of these diseases. We previously showed that FUNDC1 is a Mitophagy receptor that interacts with LC3 to mediate Mitophagy in response to hypoxia in cultured cells. We established Fundc1 knockout mouse models and used genetic and biochemical approaches, including a synthetic peptide that blocks the FUNDC1-LC3 interaction, to demonstrate that Mitophagy regulates both mitochondrial quantity and quality in vivo in response to hypoxia or hypoxic conditions caused by ischemia-reperfusion (I/R) heart injury. We found that hypoxic Mitophagy regulates platelet activities. Furthermore, we found that hypoxic preconditioning induces FUNDC1-dependent Mitophagy in p...
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Mitophagy receptor fundc1 regulates mitochondrial dynamics and Mitophagy
Autophagy, 2016Co-Authors: Ming Chen, Lei Liu, Ziheng Chen, Yueying Wang, Zheng Tan, Chongzhuo Zhu, Zhe Han, Linbo Chen, Ruize Gao, Quan ChenAbstract:ABSTRACTMitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for Mitophagy, however, the exact “coupling” of mitochondrial dynamics and Mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate Mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and Mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and Mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that ...
Weilin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Mitophagy in cardiomyocytes and in platelets a major mechanism of cardioprotection against ischemia reperfusion injury
Physiology, 2018Co-Authors: Weilin Zhang, Lei Liu, Chuyan Chen, Jing Wang, Quan ChenAbstract:Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of Mitophagy and highlight the role of Mitophagy in cardioprotection.
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Mitophagy receptor fundc1 regulates mitochondrial homeostasis and protects the heart from i r injury
Autophagy, 2017Co-Authors: Weilin Zhang, Sami Siraj, Rong Zhang, Quan ChenAbstract:ABSTRACTMitophagy plays pivotal roles in the selective disposal of unwanted mitochondria, and accumulation of damaged mitochondria has been linked to aging-related diseases. However, definitive proof that Mitophagy regulates mitochondrial quality in vivo is lacking. It is also largely unclear whether damaged mitochondria are the cause or just the consequence of these diseases. We previously showed that FUNDC1 is a Mitophagy receptor that interacts with LC3 to mediate Mitophagy in response to hypoxia in cultured cells. We established Fundc1 knockout mouse models and used genetic and biochemical approaches, including a synthetic peptide that blocks the FUNDC1-LC3 interaction, to demonstrate that Mitophagy regulates both mitochondrial quantity and quality in vivo in response to hypoxia or hypoxic conditions caused by ischemia-reperfusion (I/R) heart injury. We found that hypoxic Mitophagy regulates platelet activities. Furthermore, we found that hypoxic preconditioning induces FUNDC1-dependent Mitophagy in p...
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mitochondrial e3 ligase march5 regulates fundc1 to fine tune hypoxic Mitophagy
EMBO Reports, 2017Co-Authors: Ziheng Chen, Lei Liu, Sami Siraj, Yueying Wang, Qi Cheng, Weilin Zhang, Sheikh Arslan Sehgal, Xiaohui WangAbstract:Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC1. It is not clear whether these pathways coordinate to mediate Mitophagy in response to stresses, or how Mitophagy receptors sense stress signals to activate Mitophagy. We find that the mitochondrial E3 ligase MARCH5, but not Parkin, plays a role in regulating hypoxia-induced Mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia-induced Mitophagy, whereas knockdown of endogenous MARCH5 significantly inhibits FUNDC1 degradation and enhances mitochondrial sensitivity toward Mitophagy-inducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine-tune mitochondrial quality.
Lei Liu - One of the best experts on this subject based on the ideXlab platform.
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Mitophagy in cardiomyocytes and in platelets a major mechanism of cardioprotection against ischemia reperfusion injury
Physiology, 2018Co-Authors: Weilin Zhang, Lei Liu, Chuyan Chen, Jing Wang, Quan ChenAbstract:Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of Mitophagy and highlight the role of Mitophagy in cardioprotection.
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mitochondrial e3 ligase march5 regulates fundc1 to fine tune hypoxic Mitophagy
EMBO Reports, 2017Co-Authors: Ziheng Chen, Lei Liu, Sami Siraj, Yueying Wang, Qi Cheng, Weilin Zhang, Sheikh Arslan Sehgal, Xiaohui WangAbstract:Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC1. It is not clear whether these pathways coordinate to mediate Mitophagy in response to stresses, or how Mitophagy receptors sense stress signals to activate Mitophagy. We find that the mitochondrial E3 ligase MARCH5, but not Parkin, plays a role in regulating hypoxia-induced Mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia-induced Mitophagy, whereas knockdown of endogenous MARCH5 significantly inhibits FUNDC1 degradation and enhances mitochondrial sensitivity toward Mitophagy-inducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine-tune mitochondrial quality.
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Mitophagy receptor fundc1 regulates mitochondrial dynamics and Mitophagy
Autophagy, 2016Co-Authors: Ming Chen, Lei Liu, Ziheng Chen, Yueying Wang, Zheng Tan, Chongzhuo Zhu, Zhe Han, Linbo Chen, Ruize Gao, Quan ChenAbstract:ABSTRACTMitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for Mitophagy, however, the exact “coupling” of mitochondrial dynamics and Mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate Mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and Mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and Mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that ...
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ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate Mitophagy
EMBO reports, 2014Co-Authors: Weili Tian, Guo Chen, Lei Huang, Xingli Zhang, Peng Xue, Changqian Zhou, Lei LiuAbstract:Autophagy eliminates dysfunctional mitochondria in an intricate process known as Mitophagy. ULK1 is critical for the induction of autophagy, but its substrate(s) and mechanism of action in Mitophagy remain unclear. Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon Mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. A ULK1-binding-deficient mutant of FUNDC1 prevents ULK1 translocation to mitochondria and inhibits Mitophagy. Finally, kinase-active ULK1 and a phospho-mimicking mutant of FUNDC1 rescue Mitophagy in ULK1-null cells. Thus, we conclude that FUNDC1 regulates ULK1 recruitment to damaged mitochondria, where FUNDC1 phosphorylation by ULK1 is crucial for Mitophagy.
Lei Jiang - One of the best experts on this subject based on the ideXlab platform.
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bnip3l nix degradation leads to Mitophagy deficiency in ischemic brains
Autophagy, 2021Co-Authors: Yanrong Zheng, Lei Jiang, Zhenghong Qin, Mengru Liu, Weidong Tang, Wenping Yan, Ming Cao, Wanqing Zheng, Feng Han, Liang FangAbstract:Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient Mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a Mitophagy receptor, was degraded by proteasomes, which led to Mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on Mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce Mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the Mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked the loss of BNIP3L and subsequently promoted Mitophagy in ischemic brains. In addition, the dimeric form of BNIP3L was more prone to be degraded than its monomeric form. Carfilzomib, a drug for multiple myeloma therapy that inhibits proteasomes, reversed the BNIP3L degradation and restored Mitophagy in ischemic brains. This treatment protected against either acute or chronic ischemic brain injury. Remarkably, these effects of carfilzomib were abolished in bnip3l-/- mice. Taken together, the present study linked BNIP3L degradation by proteasomes with Mitophagy deficiency in cerebral ischemia. We propose carfilzomib as a novel therapy to rescue ischemic brain injury by preventing BNIP3L degradation.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ATG7: autophagy related 7; BCL2L13: BCL2-like 13 (apoptosis facilitator); BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CFZ: carfilzomib; COX4I1: cytochrome c oxidase subunit 4I1; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; I-R: ischemia-reperfusion; MAP1LC3A/LC3A: microtube-associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtube-associated protein 1 light chain 3 beta; O-R: oxygen and glucose deprivation-reperfusion; OGD: oxygen and glucose deprivation; PHB2: prohibitin 2; pMCAO: permanent middle cerebral artery occlusion; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PT: photothrombosis; SQSTM1: sequestosome 1; tMCAO: transient middle cerebral artery occlusion; TOMM20: translocase of outer mitochondrial membrane 20; TTC: 2,3,5-triphenyltetrazolium hydrochloride.
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bnip3l nix mediated Mitophagy protects against ischemic brain injury independent of park2
Autophagy, 2017Co-Authors: Yang Yuan, Yanrong Zheng, Xiangnan Zhang, Ying Chen, Xiaoli Wu, Jiaying Wu, Zhe Shen, Lei Jiang, Lu Wang, Wei YangAbstract:ABSTRACTCerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by Mitophagy. Here, we identified the involvement of BNIP3L/NIX in cerebral ischemia-reperfusion (I-R)-induced Mitophagy. Bnip3l knockout (bnip3l−/−) impaired Mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2−/− mice, which showed Mitophagy deficiency after I-R. Interestingly, bnip3l and park2 double-knockout mice showed a synergistic Mitophagy deficiency with I-R treatment, which further highlighted the roles of BNIP3L-mediated Mitophagy as being independent from PARK2. Further experiments indicated that phosphorylation of BNIP3L serine 81 is critical for BNIP3L-mediated Mitophagy. Nonphosphorylatable mutant BNIP3LS81A failed to counteract both Mitophagy impairment and neuroprotective effects in bnip3l−/− mice. Our findings offer insights into mitochon...
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fundc1 regulates mitochondrial dynamics at the er mitochondrial contact site under hypoxic conditions
The EMBO Journal, 2016Co-Authors: Chunxia Lin, Lei Jiang, Xiaojing Wang, Haixia Zhuang, Xingliang Zhang, Hao Chen, Yue Yang, Jingjing WangAbstract:In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called Mitophagy. The ER-mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent Mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As Mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and Mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and Mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells.
Yanrong Zheng - One of the best experts on this subject based on the ideXlab platform.
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bnip3l nix degradation leads to Mitophagy deficiency in ischemic brains
Autophagy, 2021Co-Authors: Yanrong Zheng, Lei Jiang, Zhenghong Qin, Mengru Liu, Weidong Tang, Wenping Yan, Ming Cao, Wanqing Zheng, Feng Han, Liang FangAbstract:Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient Mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a Mitophagy receptor, was degraded by proteasomes, which led to Mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on Mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce Mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the Mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked the loss of BNIP3L and subsequently promoted Mitophagy in ischemic brains. In addition, the dimeric form of BNIP3L was more prone to be degraded than its monomeric form. Carfilzomib, a drug for multiple myeloma therapy that inhibits proteasomes, reversed the BNIP3L degradation and restored Mitophagy in ischemic brains. This treatment protected against either acute or chronic ischemic brain injury. Remarkably, these effects of carfilzomib were abolished in bnip3l-/- mice. Taken together, the present study linked BNIP3L degradation by proteasomes with Mitophagy deficiency in cerebral ischemia. We propose carfilzomib as a novel therapy to rescue ischemic brain injury by preventing BNIP3L degradation.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ATG7: autophagy related 7; BCL2L13: BCL2-like 13 (apoptosis facilitator); BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CFZ: carfilzomib; COX4I1: cytochrome c oxidase subunit 4I1; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; I-R: ischemia-reperfusion; MAP1LC3A/LC3A: microtube-associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtube-associated protein 1 light chain 3 beta; O-R: oxygen and glucose deprivation-reperfusion; OGD: oxygen and glucose deprivation; PHB2: prohibitin 2; pMCAO: permanent middle cerebral artery occlusion; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PT: photothrombosis; SQSTM1: sequestosome 1; tMCAO: transient middle cerebral artery occlusion; TOMM20: translocase of outer mitochondrial membrane 20; TTC: 2,3,5-triphenyltetrazolium hydrochloride.
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bnip3l nix mediated Mitophagy protects against ischemic brain injury independent of park2
Autophagy, 2017Co-Authors: Yang Yuan, Yanrong Zheng, Xiangnan Zhang, Ying Chen, Xiaoli Wu, Jiaying Wu, Zhe Shen, Lei Jiang, Lu Wang, Wei YangAbstract:ABSTRACTCerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by Mitophagy. Here, we identified the involvement of BNIP3L/NIX in cerebral ischemia-reperfusion (I-R)-induced Mitophagy. Bnip3l knockout (bnip3l−/−) impaired Mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2−/− mice, which showed Mitophagy deficiency after I-R. Interestingly, bnip3l and park2 double-knockout mice showed a synergistic Mitophagy deficiency with I-R treatment, which further highlighted the roles of BNIP3L-mediated Mitophagy as being independent from PARK2. Further experiments indicated that phosphorylation of BNIP3L serine 81 is critical for BNIP3L-mediated Mitophagy. Nonphosphorylatable mutant BNIP3LS81A failed to counteract both Mitophagy impairment and neuroprotective effects in bnip3l−/− mice. Our findings offer insights into mitochon...
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research progress on mechanism of nix mediated Mitophagy
Journal of Zhejiang University (Medical Sciences), 2017Co-Authors: Yanrong Zheng, Xiangnan Zhang, Zhong ChenAbstract:Abstract Autophagy is fundamental to maintain cellular homeostasis. As one kind of the most well-studied selective autophagy, autophagy of mitochondria (Mitophagy)is crucial for the clearance of damaged mitochondria. Mitophagy dysfunction has been proved to be closely associated with many human diseases. Nix is a key protein for Mitophagy during the maturation of reticulocytes. However, the detailed molecular mechanisms underlying Nix-mediated Mitophagy are not fully understood. This article summarizes three possible working models of Nix in Mitophagy induction. Firstly, Nix can interplay with Parkin, another important protein for Mitophagy, to initiate Mitophagy. Secondly, Nix can serve as a receptor for autophagy machinery by interacting with Atg8 family through its LIR motif. Finally, as a BH3-only protein, Nix can compete with Beclin-1 to bind other members of Bcl-2 family resulting in increased free Beclin-1 in cytosol, which further promotes autophagy flux.