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Zambarlal Bhujabal, Åsa B Birgisdottir, Eva Sjøttem, Hanne B Brenne, Aud Øvervatn, Sabrina Habisov, Vladimir Kirkin, Trond Lamark, Terje Johansen
Mitophagy, the selective removal of damaged or excess mitochondria by autophagy, is an important process in cellular homeostasis. The outer mitochondrial membrane (OMM) proteins NIX, BNIP3, FUNDC1, and Bcl2-L13 recruit ATG8 proteins (LC3/GABARAP) to mitochondria during mitophagy. FKBP8 (also known as FKBP38), a unique member of the FK506-binding protein (FKBP) family, is similarly anchored in the OMM and acts as a multifunctional adaptor with anti-apoptotic activity. In a yeast two-hybrid screen, we identified FKBP8 as an ATG8-interacting protein...
April 5, 2017: EMBO Reports
Pierre Vigié, Nadine Camougrand
Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cells. Mitochondrial dysfunctions are implicated in numerous diseases. Therefore, maintenance of a healthy pool of mitochondria is required for cellular function and survival. Mitochondrial quality control is achieved through several mechanisms that act at different levels: proteases and chaperones, the Ubiquitin-Proteasome-System (UPS) and mitophagy. Multiple mitophagy-involved programs operate independently or undergo crosstalk, and require modulated receptor activities at the outer membranes of mitochondria...
March 2017: Médecine Sciences: M/S
Weilin Zhang, Sami Siraj, Rong Zhang, Quan Chen
Mitophagy 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...
March 21, 2017: Autophagy
Won Hee Jang, Young Joo Jeong, Sun Hee Choi, Sang-Hwa Urm, Dae-Hyun Seog
Kinesin 1 is a member of the kinesin superfamily proteins (KIFs) of microtubule-dependent molecular motor proteins that transport organelles and protein complexes in cells. Kinesin 1 consists of a homo- or hetero-dimer of kinesin heavy chains (KHCs), often, although not always, associated with two kinesin light chains (KLCs). KLCs are non-motor proteins that associate with many different binding proteins and cargoes, but their binding partners have not yet been fully identified. In the present study, a yeast two-hybrid system was used to identify proteins that interact with the tetratricopeptide repeat (TPR) domain of KLC1...
January 2017: Biomedical Reports
Ziheng Chen, Lei Liu, Qi Cheng, Yanjun Li, Hao Wu, Weilin Zhang, Yueying Wang, Sheikh Arslan Sehgal, Sami Siraj, Xiaohui Wang, Jun Wang, Yushan Zhu, Quan Chen
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...
March 2017: EMBO Reports
Weilin Zhang, He Ren, Chunling Xu, Chongzhuo Zhu, Hao Wu, Dong Liu, Jun Wang, Lei Liu, Wei Li, Qi Ma, Lei Du, Ming Zheng, Chuanmao Zhang, Junling Liu, Quan Chen
Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice...
December 20, 2016: ELife
Mengqi Lv, Chongyuan Wang, Fudong Li, Junhui Peng, Bin Wen, Qingguo Gong, Yunyu Shi, Yajun Tang
Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 (FUNDC1) was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with microtubule-associated protein light chain 3 beta (LC3B) through its LC3 interaction region (LIR). Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy...
January 2017: Protein & Cell
Maya Z Springer, Kay F Macleod
Mitophagy is a selective form of macro-autophagy in which mitochondria are specifically targeted for autophagic degradation. Mitophagy plays an important role in cellular homeostasis by eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to stress. Cells execute mitophagy through several non-redundant mechanisms, including the PINK1/Parkin partnership, which modulates turnover of depolarized mitochondria, and stress-induced BNIP3, NIX, and FUNDC1 molecular adaptors, which interact directly with LC3 to promote mitophagy...
November 2016: Journal of Pathology
Wenxian Wu, Wen Li, Hao Chen, Lei Jiang, Runzhi Zhu, Du Feng
Mitochondria need to be fragmented prior to engulfment by phagophores, the precursors to autophagosomes. However, how these 2 processes are finely regulated and integrated is poorly understood. We have shown that the outer mitochondrial membrane protein FUNDC1 is a novel mitochondrial-associated membrane (MAM) protein, enriched at the MAM by interacting with the ER resident protein CANX (calnexin) under hypoxia. As mitophagy proceeds, it dissociates from CANX and preferably recruits DNM1L/DRP1 to drive mitochondrial fission in response to hypoxic stress...
September 2016: Autophagy
Wenxian Wu, Chunxia Lin, Keng Wu, Lei Jiang, Xiaojing Wang, Wen Li, Haixia Zhuang, Xingliang Zhang, Hao Chen, Shupeng Li, Yue Yang, Yue Lu, Jingjing Wang, Runzhi Zhu, Liangqing Zhang, Senfang Sui, Ning Tan, Bin Zhao, Jingjing Zhang, Longxuan Li, Du Feng
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...
July 1, 2016: EMBO Journal
Tao Tan, Marcel Zimmermann, Andreas S Reichert
Mitophagy is a selective autophagy pathway conserved in eukaryotes and plays an essential role in mitochondrial quality and quantity control. Mitochondrial fission and fusion cycles maintain a certain amount of healthy mitochondria and allow the isolation of damaged mitochondria for their elimination by mitophagy. Mitophagy can be classified into receptor-dependent and ubiquitin-dependent pathways. The mitochondrial outer membrane protein Atg32 is identified as the only known receptor for mitophagy in baker's yeast, whereas mitochondrial proteins FUNDC1, NIX/BNIP3L, BNIP3 and Bcl2L13 are recognized as mitophagy receptors in mammalian cells...
July 1, 2016: Biological Chemistry
Haiyang Liu, Hong Zhu, Tong Li, Pengfei Zhang, Ning Wang, Xiaodong Sun
PURPOSE: This study investigated the neuroprotective effect against photoreceptor cell death using prolyl-4-hydroxylases inhibitor (PHI), an HIF-1α stabilizer, in experimental retinal detachment (RD). METHODS: RD was created in Brown Norway rats by subretinal injection of 1% sodium hyaluronate. FG-4592 (a PHI, 25 mg/kg) or a vehicle was administered every 2 days with retro-orbital injection. Photoreceptor death was evaluated by TdT-dUTP terminal nick-end labeling (TUNEL) assay 3 days after RD and by the thickness of the outer nuclear layer 7 days after RD...
April 2016: Investigative Ophthalmology & Visual Science
Ming Chen, Ziheng Chen, Yueying Wang, Zheng Tan, Chongzhuo Zhu, Yanjun Li, Zhe Han, Linbo Chen, Ruize Gao, Lei Liu, Quan Chen
Mitochondrial 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...
2016: Autophagy
Hao Wu, Danfeng Xue, Guo Chen, Zhe Han, Li Huang, Chongzhuo Zhu, Xiaohui Wang, Haijing Jin, Jun Wang, Yushan Zhu, Lei Liu, Quan Chen
Receptor-mediated mitophagy is one of the major mechanisms of mitochondrial quality control essential for cell survival. We previously have identified FUNDC1 as a mitophagy receptor for selectively removing damaged mitochondria in mammalian systems. A critical unanswered question is how receptor-mediated mitophagy is regulated in response to cellular and environmental cues. Here, we report the striking finding that BCL2L1/Bcl-xL, but not BCL2, suppresses mitophagy mediated by FUNDC1 through its BH3 domain. Mechanistically, we demonstrate that BCL2L1, but not BCL2, interacts with and inhibits PGAM5, a mitochondrially localized phosphatase, to prevent the dephosphorylation of FUNDC1 at serine 13 (Ser13), which activates hypoxia-induced mitophagy...
October 1, 2014: Autophagy
Lei Liu, Kaori Sakakibara, Quan Chen, Koji Okamoto
Mitophagy, or mitochondria autophagy, plays a critical role in selective removal of damaged or unwanted mitochondria. Several protein receptors, including Atg32 in yeast, NIX/BNIP3L, BNIP3 and FUNDC1 in mammalian systems, directly act in mitophagy. Atg32 interacts with Atg8 and Atg11 on the surface of mitochondria, promoting core Atg protein assembly for mitophagy. NIX/BNIP3L, BNIP3 and FUNDC1 also have a classic motif to directly bind LC3 (Atg8 homolog in mammals) for activation of mitophagy. Recent studies have shown that receptor-mediated mitophagy is regulated by reversible protein phosphorylation...
July 2014: Cell Research
Guo Chen, Zhe Han, Du Feng, Yanfang Chen, Linbo Chen, Hao Wu, Li Huang, Changqian Zhou, Xiangyu Cai, Changying Fu, Liangwei Duan, Xiaohui Wang, Lei Liu, Xinqi Liu, Yuequan Shen, Yushan Zhu, Quan Chen
Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment...
May 8, 2014: Molecular Cell
Wenxian Wu, Weili Tian, Zhe Hu, Guo Chen, Lei Huang, Wen Li, Xingli Zhang, Peng Xue, Changqian Zhou, Lei Liu, Yushan Zhu, Xingliang Zhang, Longxuan Li, Liangqing Zhang, Senfang Sui, Bin Zhao, Du Feng
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...
May 2014: EMBO Reports
Wen Li, Xingli Zhang, Haixia Zhuang, He-ge Chen, Yinqin Chen, Weili Tian, Wenxian Wu, Ying Li, Sijie Wang, Liangqing Zhang, Yusen Chen, Longxuan Li, Bin Zhao, Senfang Sui, Zhe Hu, Du Feng
Mitophagy receptors mediate the selective recognition and targeting of damaged mitochondria by autophagosomes. The mechanism for the regulation of these receptors remains unknown. Here, we demonstrated that a novel hypoxia-responsive microRNA, microRNA-137 (miR-137), markedly inhibits mitochondrial degradation by autophagy without affecting global autophagy. miR-137 targets the expression of two mitophagy receptors NIX and FUNDC1. Impaired mitophagy in response to hypoxia caused by miR-137 is reversed by re-expression of FUNDC1 and NIX expression vectors lacking the miR-137 recognition sites at their 3' UTR...
April 11, 2014: Journal of Biological Chemistry
Du Feng, Lei Liu, Yushan Zhu, Quan Chen
Mitochondrial autophagy or mitophagy is a cellular metabolic pathway that mediates the selective elimination of dysfunctional or unwanted mitochondria. Considerable advancements have been made to elucidate the molecular mechanism behind mitophagy, particularly Parkin-mediated mitophagy. Several mitophagy receptors have been discovered in different physiological settings, including ATG32 in yeast as well as NIX, BNIP3, and FUNDC1 in mammalian cells. However, the signaling events that regulate these mitophagy receptors and their physiological significance in human diseases are poorly understood...
July 15, 2013: Experimental Cell Research
Lei Liu, Du Feng, Guo Chen, Ming Chen, Qiaoxia Zheng, Pingping Song, Qi Ma, Chongzhuo Zhu, Rui Wang, Wanjun Qi, Lei Huang, Peng Xue, Baowei Li, Xiaohui Wang, Haijing Jin, Jun Wang, Fuquan Yang, Pingsheng Liu, Yushan Zhu, Senfang Sui, Quan Chen
Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy...
February 2012: Nature Cell Biology
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