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Literature Report

Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.

Juliet Goldsmith | Alban Ordureau | J Wade Harper | Erika L F Holzbaur

Neuron | 2022

Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.

Pubmed ID: 35051374

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Associated grants

Agency: NINDS NIH HHS, United States
Id: R01 NS083524
Agency: NINDS NIH HHS, United States
Id: R37 NS060698
Agency: NINDS NIH HHS, United States
Id: R37 NS083524
Agency: NINDS NIH HHS, United States
Id: R01 NS060698
Agency: NINDS NIH HHS, United States
Id: R01 NS110395

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