ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy |
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| Authors: | 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 |
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| Institution: | 1. Institute of Neurology, Guangdong Key Laboratory of Age‐related Cardiac‐cerebral Vascular Disease, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, China;2. Department of Anesthesiology, Guangdong Medical College, Zhanjiang, China;3. College of Life Sciences, Nankai University, Tianjin, China;4. Cell Biology Core Facility, Center for Biomedical Analysis, Tsinghua University, Beijing, China;5. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;6. State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;7. Department of Pediatrics, Guangdong Medical College, Zhanjiang, China;8. Department of Neurology, Gongli Hospital, Pudong New Area, Shanghai, China;9. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China |
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| Abstract: | 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. |
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| Keywords: | FUNDC1 mitochondria mitochondrial quality control mitophagy ULK1 |
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