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

## TL;DR

This study shows that the enzyme SET-18/SMYD2 promotes aging by increasing mitochondrial reactive oxygen species through activation of the NADase TIR-1d/SARM1.

## Contribution

Identifies a conserved 'H3K36me2-NADase-mtROS' signaling axis linking nuclear histone modification to mitochondrial aging.

## Key findings

- SET-18/SMYD2 increases mtROS levels in C. elegans and mouse muscle, promoting aging.
- SET-18/SMYD2 activates TIR-1d/SARM1 via H3K36me2 modification, reducing NAD+ and increasing mtROS.
- The H3K36me2-NADase-mtROS axis is conserved from worms to mammals and accelerates muscle aging.

## Abstract

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 C. elegans 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 tir-1 isoform d (tir-1d)/sarm1 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 C. elegans to mammals.

•SET-18/SMYD2 increases mtROS level to promote aging of C. elegans and mouse muscle•SET-18/SMYD2 targets NADase TIR-1d/SARM1 to enhance mtROS accumulation to accelerate aging•SET-18/SMYD2 activates NADase TIR-1d/SARM1 expression through histone H3K36me2 modification

SET-18/SMYD2 increases mtROS level to promote aging of C. elegans and mouse muscle

SET-18/SMYD2 targets NADase TIR-1d/SARM1 to enhance mtROS accumulation to accelerate aging

SET-18/SMYD2 activates NADase TIR-1d/SARM1 expression through histone H3K36me2 modification

Biochemistry; Molecular biology; Cell biology