Lysosomal degradation of depolarized mitochondria is rate-limiting in OPTN-dependent neuronal mitophagy.

Autophagy
Chantell S Evans, Erika Lf Holzbaur

Abstract

Damaged mitochondria are selectively removed from the cell in a process termed mitophagy. This mitochondrial quality control mechanism is important for neuronal homeostasis, and mutations in pathway components are causative for Parkinson disease and amyotrophic lateral sclerosis (ALS). Here, we discuss our recent work using a novel mild induction paradigm to investigate the spatiotemporal dynamics of mitophagy in primary neurons. Using live-cell imaging, we find that mitophagy-associated proteins translocate to depolarized mitochondrial fragments. These mitophagic events were primarily localized to somatodendritic compartments, suggesting neuronal mitophagy is primarily a somal quality control mechanism. Damaged mitochondria were efficiently sequestered within autophagosomes, but lysosomal fusion or acidification was significantly delayed. Surprisingly, engulfed mitochondria persisted in non-acidified vesicular compartments for hours to days after initial damage. Expression of an ALS-associated mutation disrupted the membrane potential of the mitochondrial network, and oxidative stress exacerbated this effect. Importantly, our results highlight the slow kinetics of mitophagy and suggest that slow turnover of damaged mitochondri...Continue Reading

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Citations

Oct 18, 2020·Biomedicines·Maria EjmaGjumrakch Aliev
Jan 17, 2021·International Journal of Molecular Sciences·Enrique MadrugaAna Martínez
Feb 21, 2021·Development·Tierney Baum, Vivian Gama
Apr 25, 2021·Science Advances·Chunmei ChangJames H Hurley
May 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Tzu-Huai LinMarc R Freeman

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