Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

Abstract

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2{beta} was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2{beta} phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2{beta} expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2{beta} axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases. HighlightsO_LILoss of axonal mitochondria impairs autophagy and accumulates proteins in the axon C_LIO_LILoss of axonal mitochondria increases eIF2{beta} and decreases p-eIF2 C_LIO_LINeuronal upregulation of eIF2{beta} induces autophagic defects and locomotor dysfunction C_LIO_LILowering eIF2{beta} rescues autophagic defects caused by loss of axonal mitochondria C_LI