SUMO Wrestles with Mitophagy to Extend Lifespan

Abstract

SUMOylation, a conserved protein post-translational modification that performs multiple functions including regulation of nuclear transport and transcription, is implicated in numerous biological processes including aging. RNAi knockdown of the sole Small Ubiquitin-like MOdifier (SUMO) gene, smo-1, in Caenorhabditis elegans shortened lifespan, whereas overexpression in the intestine modestly increased lifespan. Smo-1 is required for mitochondrial fission in a tissue-specific manner. Fission, in turn, is needed for mitophagy to maintain mitochondrial homeostasis during aging. SUMOlyation affects DAuer Formation (DAF)-16, which can be directly SUMOylated, and SKN-1, the homolog of mammalian Nrf2. These regulators play key roles in maintaining mitochondrial homeostasis. However, given the modest effect of overexpressing smo-1 on lifespan enhancement and potential interference with other genes that can promote increased lifespan, caution is advised in the translation of this study based on C. elegans. Although inhibitors of SUMOlyation have been developed for cancer and activators also have been identified, broad-acting biochemical pathway modifiers such as SUMO are often suboptimal drug targets and may not be as promising for antiaging applications as they first appear.