Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

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

doi:10.1038/ncb2422

Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

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 SuiQuan Chen^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

1307 Scopus citations

Abstract

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. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction- deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

Original language	English (US)
Pages (from-to)	177-185
Number of pages	9
Journal	Nature Cell Biology
Volume	14
Issue number	2
DOIs	https://doi.org/10.1038/ncb2422
State	Published - Feb 2012

Funding

We wish to thank H. Zhang from the National Institute of Biological Sciences, China, and L. Yu from Tsinghua University, China, for their suggestions and critical reading of the manuscript. We thank Y. G. Chen from Tsinghua University for providing PGEX4T1-GABARAP and PGEX4T1-GABARAPL2 constructs. We wish to thank M. Bartlam from Nankai University and A. Zhou from Cleveland State University in Ohio for improvement of the English of the manuscript. The Chen laboratory was supported by the 973 project of the Ministry of Science and Technology (China) (2011CB910903 and 2010CB912204) and by grants from the National Natural Science Foundation of China (81130045, 90713006).

ASJC Scopus subject areas

Cell Biology

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10.1038/ncb2422

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title = "Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells",

abstract = "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. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction- deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.",

author = "Lei Liu and Du Feng and Guo Chen and Ming Chen and Qiaoxia Zheng and Pingping Song and Qi Ma and Chongzhuo Zhu and Rui Wang and Wanjun Qi and Lei Huang and Peng Xue and Baowei Li and Xiaohui Wang and Haijing Jin and Jun Wang and Fuquan Yang and Pingsheng Liu and Yushan Zhu and Senfang Sui and Quan Chen",

note = "Funding Information: We wish to thank H. Zhang from the National Institute of Biological Sciences, China, and L. Yu from Tsinghua University, China, for their suggestions and critical reading of the manuscript. We thank Y. G. Chen from Tsinghua University for providing PGEX4T1-GABARAP and PGEX4T1-GABARAPL2 constructs. We wish to thank M. Bartlam from Nankai University and A. Zhou from Cleveland State University in Ohio for improvement of the English of the manuscript. The Chen laboratory was supported by the 973 project of the Ministry of Science and Technology (China) (2011CB910903 and 2010CB912204) and by grants from the National Natural Science Foundation of China (81130045, 90713006).",

year = "2012",

month = feb,

doi = "10.1038/ncb2422",

language = "English (US)",

volume = "14",

pages = "177--185",

journal = "Nature Cell Biology",

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AU - Liu, Lei

AU - Feng, Du

AU - Chen, Guo

AU - Chen, Ming

AU - Zheng, Qiaoxia

AU - Song, Pingping

AU - Ma, Qi

AU - Zhu, Chongzhuo

AU - Wang, Rui

AU - Qi, Wanjun

AU - Huang, Lei

AU - Xue, Peng

AU - Li, Baowei

AU - Wang, Xiaohui

AU - Jin, Haijing

AU - Wang, Jun

AU - Yang, Fuquan

AU - Liu, Pingsheng

AU - Zhu, Yushan

AU - Sui, Senfang

AU - Chen, Quan

N1 - Funding Information: We wish to thank H. Zhang from the National Institute of Biological Sciences, China, and L. Yu from Tsinghua University, China, for their suggestions and critical reading of the manuscript. We thank Y. G. Chen from Tsinghua University for providing PGEX4T1-GABARAP and PGEX4T1-GABARAPL2 constructs. We wish to thank M. Bartlam from Nankai University and A. Zhou from Cleveland State University in Ohio for improvement of the English of the manuscript. The Chen laboratory was supported by the 973 project of the Ministry of Science and Technology (China) (2011CB910903 and 2010CB912204) and by grants from the National Natural Science Foundation of China (81130045, 90713006).

PY - 2012/2

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N2 - 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. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction- deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

AB - 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. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction- deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

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JF - Nature Cell Biology

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ER -

Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

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