MAK-2 Kinase Is Required for Extended Longevity and Enhanced Stress Resistance Resulting From Mild Impairment of Mitochondrial Function in isp-1 Mutants.

Although mitochondrial function is essential for life in multicellular organisms, work from multiple model organisms has demonstrated that a mild impairment of mitochondrial function can increase lifespan. In C. elegans, a mutation in the isp-1 gene, which encodes the Rieske iron sulfur protein in Complex III of the mitochondrial electron transport chain, results in increased lifespan, enhanced resistance to stress and slow physiologic rates. While the molecular mechanisms involved are incompletely understood, our working model is that altered mitochondrial function and increased levels of reactive oxygen species lead to changes in nuclear gene expression, including the upregulation of cellular resilience pathways, through mitochondria-to-nucleus signaling. In this work, we examine the role of the kinase MAK-2 and other kinase signaling pathways in the lifespan and stress resistance of isp-1 worms. We find that disruption of mak-2 specifically decreases the lifespan and stress resistance of isp-1 mutants while having no effect on wild-type animals. Interestingly, kinases from a parallel signaling pathway (MLK-1/MEK-1/KGB-1) are also required for the long-lifespan of isp-1 worms. Finally, we used RNA sequencing to define the role of MAK-2 in mediating the gene expression changes in isp-1 worms. We found that many of the genes that are significantly modulated in isp-1 worms are dependent on MAK-2 including genes involved in innate immunity and stress response. Overall, this work demonstrates an important role for kinase signaling in mediating the lifespan extension and enhanced stress resistance resulting from the mild impairment of mitochondrial function.