Mitochondria-targeting hydrogen sulfide donors prolong healthspan: lifespan ratio in Caenorhabditis elegans

摘要

Progressive muscle atrophy is characteristic of several chronic debilitating conditions, including ageing (sarcopenia), muscular dystrophies, diabetes, bedrest and spaceflight. Whilst the precise mechanisms of slow atrophy are poorly defined and multifactorial, impaired mitochondrial ‘function’ (e.g. oxidative capacity and fusion-fission dynamics) is a common feature and represents an attractive target for therapy. Nonetheless, effective countermeasures remain elusive. Hydrogen sulfide (H 2 S) is an endogenous ‘gasotransmitter’ with important roles in several biochemical processes, including the maintenance of mitochondrial integrity, and in models of ageing ‘H 2 S bioavailability’ is significantly reduced. Using Caenorhabditis elegans as an established model for muscle ageing, we have examined the role of a novel class of H 2 S donors for promoting healthspan and lifespan. Unlike general non-targeted H 2 S donor compounds with established efficacy in extending lifespan (e.g. GYY4137), we have examined compounds that drive targeted H 2 S directly to the mitochondria by coupling H 2 S-generating moieties to a triphenylphosphonium motif (AP39) or mitochondria-targeting peptide sequences (RTP10). Our study shows that these compounds effectively preserve mitochondrial structure versus non-targeted H 2 S donors (mitochondria::GFP fragmentation: AP39 = ≥10 d, GYY4137 = 6 d post-adulthood). Mitochondrial H 2 S also improved animal movement rate (movement across the lifespan (mean ± SEM): AP39 = 73.2 ± 9.6, GYY4137 = 57.6 ± 27.6 strokes.min -1 , P P 2 S donors (e.g. ≤ 100 nM vs.≥50 μM). Our study strongly suggests that enhancing mitochondrial function via exogenous mitochondria-targeting H 2 S might be an effective treatment strategy for preserving muscle health during ageing for improving the healthspan: lifespan ratio. Mitochondrial H 2 S supplementation may also hold future efficacy for other muscle mitochondrial pathologies.