The role of hydrogen sulfide supplementation in Caenorhabditis elegans ageing and disease models of mitochondrial dysfunction

Abstract

Mitochondrial dysfunction plays pivotal roles in both ageing and genetically inherited disease progression and has been a target for numerous therapeutic studies. Despite this, effective pharmacological countermeasures that augment mitochondrial function with ageing and mitochondria-specific diseases are limited. Whilst the precise mechanisms of mitochondrial pathology between these diseases likely act through distinct pathways, therapies that restore overall mitochondrial health could delay phenotypic degeneration and provide a basis for translational research. Hydrogen sulfide (H2S) is a conserved mitochondrial substrate and post translational regulator across species that once played essential roles in biochemical energy provision in pre-biotic life. Today, H2S metabolising pathways remain physically embedded in mammalian mitochondria and perform crucial signalling events required for healthy ageing. With endogenous levels of H2S known to decline with progressive ageing, muscle disease and mitochondrial pathologies, I hypothesised if targeting pharmacological H2S to mitochondria could ameliorate molecular and phenotypic perturbations across these disease states using C. elegans as a model organism. Within this thesis, i show H2S delays the loss of animal healthspan with ageing by restoring key mitochondrial, peroxisomal and global transcriptomic profiles by modulating conserved transcription-regulating circuits. Importantly, treatment onset beginning in mid-adult life continues to preserve healthspan, highlighting the therapeutic potential of mitochondrial H2S in ageing. In a model of C. elegans muscle disease, we show H2S administration restores the levels of endogenous sulfur-metabolising genes and global sulfide levels. Supplementation of a panel of nutritionally available sulfur-containing amino acids also restores sulfide levels and augments animal healthspan. Importantly, we find that sulfur amino acids improve healthspan predominantly via calcium/excitation contraction coupling vs mitochondria-predominant mechanisms seen with H2S treatments. Lastly, we find mitochondrial H2S treatments display divergent efficacy in restoring healthspan across a range of primary mitochondrial disease mutants, and can be improved by modulating mitochondria-targeting linker moieties. Additionally, we highlight dual roles of mitochondria-targeted H2S in modulating transcriptomic and/or protein post-translational profiles in healthspan deficient mitochondrial mutants, with evident differences between distinct classes of mitochondrial disease. Together, this work highlights the therapeutic potential of pharmacological/dietary modulation of the H2S/sulfur pathway across a broad setting of age-related and genetically inherited mitochondrial dysfunction. Experimentally, these data provide crucial findings for higher organism translational research