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

Etheridge, Tim and Gaffney, Christopher and Szewczyk, Nate and Torregrossa, Roberta and Wood, Mark E. and Whiteman, Matthew (2017) Mitochondria-targeting hydrogen sulfide donors prolong healthspan : lifespan ratio in Caenorhabditis elegans. Free Radical Biology and Medicine, 112 (Suppl.). p. 51. ISSN 0891-5849

Abstract

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 (H2S) is an endogenous ‘gasotransmitter’ with important roles in several biochemical processes, including the maintenance of mitochondrial integrity, and in models of ageing ‘H2S bioavailability’ is significantly reduced. Using Caenorhabditis elegans as an established model for muscle ageing, we have examined the role of a novel class of H2S donors for promoting healthspan and lifespan. Unlike general non-targeted H2S donor compounds with established efficacy in extending lifespan (e.g. GYY4137), we have examined compounds that drive targeted H2S directly to the mitochondria by coupling H2S-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 H2S donors (mitochondria::GFP fragmentation: AP39 = ≥10 d, GYY4137 = 6 d post-adulthood). Mitochondrial H2S 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 <0.01) and extended lifespan (median survival: AP39 = 10 d; GYY4137 = 8 d post-adulthood, P < 0.001). Importantly, these compounds were effective at concentrations orders of magnitude lower than traditional H2S donors (e.g. ≤ 100 nM vs.≥50 μM). Our study strongly suggests that enhancing mitochondrial function via exogenous mitochondria-targeting H2S might be an effective treatment strategy for preserving muscle health during ageing for improving the healthspan: lifespan ratio. Mitochondrial H2S supplementation may also hold future efficacy for other muscle mitochondrial pathologies.