Elevated mitochondrial superoxide promotes longevity through a mitochondria-to-nucleus kinase signaling pathway

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-2worms) using RNA sequencing.sod-2mutants 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 insod-2worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of 61 selected kinases tosod-2longevity. From this screen, we found 25 kinases which are required for the long lifespan ofsod-2mutants includingmak-2, which has an established role in a kinase signaling pathway involved in axon regeneration. Disruption ofmak-2specifically reducessod-2lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act withmak-2in pathways controlling axon regeneration, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required forsod-2longevity 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.