FUNDC1 regulates mitochondrial dynamics at the ER–mitochondrial contact site under hypoxic conditions |
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| Authors: | 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 |
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| Affiliation: | 1. Guangdong Key Laboratory of Age‐related Cardiac‐cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China;2. Department of Anesthesiology, Guangdong Medical University, Zhanjiang, China;3. Department of Pediatrics, Guangdong Medical University, Zhanjiang, China;4. Laboratory of Hepatobiliary Surgery, Zhanjiang Key Laboratory of Hepatobiliary Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China;5. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China;6. Guangdong General Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China;7. Department of Neurology, Gongli Hospital, Pudong New Area, Shanghai, China;8. Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA, USA |
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| Abstract: | 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. |
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| Keywords: | autophagy ER– mitochondrial contact site
MAM
mitochondrial fission mitophagy |
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