PMID- 33970775 OWN - NLM STAT- MEDLINE DCOM- 20220407 LR - 20220407 IS - 1554-8635 (Electronic) IS - 1554-8627 (Print) IS - 1554-8627 (Linking) VI - 17 IP - 10 DP - 2021 Oct TI - Chaperone-mediated autophagy controls the turnover of E3 ubiquitin ligase MARCHF5 and regulates mitochondrial dynamics. PG - 2923-2938 LID - 10.1080/15548627.2020.1848128 [doi] AB - As a highly dynamic organelle, mitochondria undergo constant fission and fusion to change their morphology and function, coping with various stress conditions. Loss of the balance between fission and fusion leads to impaired mitochondria function, which plays a critical role in the pathogenesis of Parkinson disease (PD). Yet the mechanisms behind mitochondria dynamics regulation remain to be fully illustrated. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process that selectively degrades proteins to maintain cellular proteostasis. In this study, we demonstrated that MARCHF5, an E3 ubiquitin ligase required for mitochondria fission, is a CMA substrate. MARCHF5 interacted with key CMA regulators and was degraded by lysosomes. Severe oxidative stress compromised CMA activity and stabilized MARCHF5, which facilitated DNM1L translocation and led to excessive fission. Increase of CMA activity promoted MARCHF5 turnover, attenuated DNM1L translocation, and reduced mitochondria fragmentation, which alleviated mitochondrial dysfunction under oxidative stress. Furthermore, we showed that conditional expression of LAMP2A, the key CMA regulator, in dopaminergic (DA) neurons helped maintain mitochondria morphology and protected DA neuronal viability in a rodent PD model. Our work uncovers a critical role of CMA in maintaining proper mitochondria dynamics, and loss of this regulatory control may occur in PD and underlie its pathogenic process.Abbreviations: CMA: chaperone-mediated autophagy; DA: dopaminergic; DNM1L: dynamin 1 like; FCCP: carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; HSPA8: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MARCHF5: membrane-associated ring-CH-type finger 5; MMP: mitochondria membrane potential; OCR: oxygen consumption rate; 6-OHDA: 6-hydroxydopamine; PD: Parkinson disease; SNc: substantia nigra pars compacta; TEM: transmission electron microscopy; TH: tyrosine hydroxylase; TMRE: tetramethylrhodamine ethyl ester perchlorate; WT: wild type. FAU - Nie, Tiejian AU - Nie T AD - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Tao, Kai AU - Tao K AD - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Zhu, Lin AU - Zhu L AD - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Huang, Lu AU - Huang L AD - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Hu, Sijun AU - Hu S AD - State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Yang, Ruixin AU - Yang R AD - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Xu, Pingyi AU - Xu P AD - Department of Neurology, First Affiliated Hospital of GuangZhou Medical University, Guangzhou, Guangdong, China. FAU - Mao, Zixu AU - Mao Z AD - Departments of Pharmacology and Chemical Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA. FAU - Yang, Qian AU - Yang Q AD - Department of Neurology, First Affiliated Hospital of GuangZhou Medical University, Guangzhou, Guangdong, China. AD - Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201201 PL - United States TA - Autophagy JT - Autophagy JID - 101265188 RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Autophagy MH - *Chaperone-Mediated Autophagy MH - Humans MH - Mitochondrial Dynamics MH - *Parkinson Disease/metabolism MH - Ubiquitin-Protein Ligases PMC - PMC8526038 OTO - NOTNLM OT - Autophagy/mitochondria/oxidative stress/Parkinson disease/proteostasis COIS- The authors declare no potential conflict of interests. EDAT- 2021/05/11 06:00 MHDA- 2022/04/08 06:00 PMCR- 2020/12/01 CRDT- 2021/05/10 17:35 PHST- 2021/05/11 06:00 [pubmed] PHST- 2022/04/08 06:00 [medline] PHST- 2021/05/10 17:35 [entrez] PHST- 2020/12/01 00:00 [pmc-release] AID - 1848128 [pii] AID - 10.1080/15548627.2020.1848128 [doi] PST - ppublish SO - Autophagy. 2021 Oct;17(10):2923-2938. doi: 10.1080/15548627.2020.1848128. Epub 2020 Dec 1.