TY - JOUR

T1 - Mitochondria-targeting hydrogen sulfide donors prolong healthspan

T2 - 24th Annual Meeting of the Society-for-Redox-Biology-and-Medicine (SfRBM)

AU - Etheridge, Tim

AU - Gaffney, Christopher

AU - Szewczyk, Nate

AU - Torregrossa, Roberta

AU - Wood, Mark E.

AU - Whiteman, Matthew

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

U2 - 10.1016/j.freeradbiomed.2017.10.067

DO - 10.1016/j.freeradbiomed.2017.10.067

M3 - Meeting abstract

VL - 112

SP - 51

EP - 51

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - Suppl. 1

Y2 - 29 November 2017 through 2 December 2017

ER -