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

Huihui Li; Zak Doric; Amandine Berthet; Danielle M Jorgens; Mai K Nguyen; Ivy Hsieh; Julia Margulis; Rebecca Fang; Jayanta Debnath; Hiromi Sesaki; Steve Finkbeiner; Eric Huang; Ken Nakamura

doi:10.1126/sciadv.abf6580

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

Sci Adv. 2021 Aug 6;7(32):eabf6580. doi: 10.1126/sciadv.abf6580. Print 2021 Aug.

Authors

Huihui Li¹, Zak Doric^{1

2}, Amandine Berthet¹, Danielle M Jorgens³, Mai K Nguyen¹, Ivy Hsieh⁴, Julia Margulis¹, Rebecca Fang^{1

2}, Jayanta Debnath^{4

5}, Hiromi Sesaki⁶, Steve Finkbeiner^{2

5

7

8

9}, Eric Huang^{2

4

5}, Ken Nakamura^{10

2

5

8}

Affiliations

¹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
² Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Electron Microscope Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
⁷ Center for Systems and Therapeutics, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁰ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA. ken.nakamura@gladstone.ucsf.edu.

Abstract

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).

Abstract

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