Investigating Mechanisms by Which Mitochondrial Superoxide Promotes Longevity
Many approaches to modestly slow aging in short-lived species involve a mild mitochondrial dysfunction that that somewhat increases the level of reactive oxygen species generated in the course of producing adenosine triphosphate (ATP) to power the cell. Reactive oxygen species react with and damage molecular machinery throughout the cell, damage that needs to be repaired. The cell reacts with an increase in repair and maintenance activities that address oxidative damage and other forms of damage, producing a net benefit to function. Here, researchers investigate one portion of how this response is regulated, looking at the metabolism of nematode worms.
The reactive oxygen species superoxide is generated by mitochondria during the process of producing energy. While superoxide can cause oxidative damage to the cell, we and others have shown that a mild increase in mitochondrial superoxide extends longevity in multiple model organisms. To elucidate the molecular mechanisms involved, we identified transcriptional changes in mitochondrial superoxide dismutase deletion mutants (sod-2 worms) using RNA sequencing. sod-2 mutants exhibit a number of changes in nuclear gene expression resulting from elevated mitochondrial superoxide suggesting that mitochondria-to-nucleus signaling is contributing to their longevity.
Gene ontology enrichment analysis demonstrated that genes involved in innate immunity and cuticle formation are significantly upregulated in sod-2 worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of selected kinases to sod-2 longevity. From this screen, we found 25 kinases which are required for the long lifespan of sod-2 mutants including mak-2, which has a role in a kinase signaling pathway involved in axon regeneration. Disruption of mak-2 specifically reduces sod-2 lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act with mak-2 in established signaling pathways, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required for sod-2 longevity but not wild-type lifespan.
Combined these results suggest a novel role for kinases with established roles in axon regeneration in promoting longevity through a mitochondria-to-nucleus signaling pathway.