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

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 mitochondria may increase neuronal susceptibility to neurodegeneration.

KEYWORDS:

• Autophagy
• mitophagy
• mitochondria
• lysosome
• neurodegenerative diseases

Disclosure statement

The authors declare no competing financial interests.

Additional information

Funding

This work was supported by a grant from NIH NINDS [R37 NS060698] to E.L.F.H. C.S.E. was supported by the Howard Hughes Medical Institute Hanna H. Gray Fellowship