Mitochondrial dysfunction is a prominent feature of aging, particularly in tissues with high energy requirements, such as muscles and the brain. Part of the problem is that autophagy to clear out damaged mitochondria becomes less effective. Here researchers show that the distribution of mitochondria in neurons is important to the operation of autophagy and mitochondrial function. Unlike other cells, neurons have very long projections, the axons, that require a sufficiently large population of localized mitochondria for correct function. Aging impairs the mechanisms involved in ensuring that axons are sufficiently supplied with mitochondria, and this in turn impairs function in the brain.
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 eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.
