Histone methyltransferase SET-18/SMYD2-mediated activation of NADase TIR-1d/SARM1 increases mtROS to promote aging

Histone lysine methylation regulates the expressions of mitochondrial function-related genes, which presents a "nucleus-to-mitochondria" signal communication, playing a key role in aging control. However, the underlying mechanisms remain elusive due to the complexity of histone lysine methylation in transcription modulation. In this study, using <i>C. elegans</i> and mouse C2C12 cell-differentiated myotubes as research models, we found that histone H3K36me2 methyltransferase SET-18/SMYD2 were responsible for the increase of mitochondrial reactive oxygen species (mtROS) accumulation during aging. Mechanistically, SET-18/SMYD2-mediated H3K36me2 modification upregulated the expression of NADase <i>tir-1 isoform d</i> (<i>tir-1d</i>)/<i>sarm1</i> to decrease NAD⁺ level. Consequently, mtROS level was elevated, which resulted in shortened worm lifespan as well as accelerated mouse myotubes atrophy (a hallmark of muscle aging). These findings proposed that mtROS generation is actively regulated other than passively accumulated in aging process, and revealed a "H3K36me2-NADase-mtROS" signaling axis of "nucleus-to-mitochondria" communication to modulate aging, which is conserved from <i>C. elegans</i> to mammals.