Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.

Autor:	Li H; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA., Doric Z; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.; Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA., Berthet A; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA., Jorgens DM; Electron Microscope Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA., Nguyen MK; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA., Hsieh I; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA., Margulis J; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA., Fang R; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.; Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA., Debnath J; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.; Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA., Sesaki H; Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA., Finkbeiner S; Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.; Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Center for Systems and Therapeutics, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA., Huang E; Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.; Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA., Nakamura K; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA. ken.nakamura@gladstone.ucsf.edu.; Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.; Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 Aug 06; Vol. 7 (32). Date of Electronic Publication: 2021 Aug 06 (Print Publication: 2021).
DOI:	10.1126/sciadv.abf6580
Abstrakt:	Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson's disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu