Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

Abstract

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while cellular factors that trigger it are not 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 eIF2beta was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2alpha, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2beta phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2beta expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2beta axis maintains proteostasis in the axon, of which disruption may underly the onset and progression of age-related neurodegenerative diseases.