Mild Mitochondrial Impairment Activates Overlapping Longevity Pathways Converging on the Flavin-Containing Monooxygenase FMO-2

A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of <i>fmo-2</i> in the long lifespan of genetic mitochondrial mutants in <i>C. elegans</i>. We found that <i>fmo-2</i>, but not other <i>fmo</i> genes, are specifically upregulated in the long-lived mitochondrial mutants <i>clk-1, isp-1</i> and <i>nuo-6</i>. Disruption of <i>fmo-2</i> through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that <i>fmo-2</i> is required for lifespan extension in these worms. Moreover, signaling molecules that have been shown to be involved in upregulation of <i>fmo-2</i> are also required for the long life of <i>clk-1, isp-1</i> and <i>nuo-6</i> mutants including HLH-30, NHR-49 and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in <i>clk-1</i> mutants on the expression of <i>fmo-2</i>. We found that in all cases, genes required for <i>clk-1</i> longevity are also required for the upregulation of <i>fmo-2</i> in <i>clk-1</i> worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.