Slade, Luke et al. (2021) International Worm Meeting "The Mitochondria-targeted hydrogen sulfide delivery improves health and mitochondrial function in a C. elegans primary mitochondrial disease model"

Whiteman, Matthew, Etheridge, Timothy, Slade, Luke, Torregrossa, Roberta

[International Worm Meeting, 2021]

Introduction: Primary mitochondrial diseases (PMD) are genetically inherited disorders culminating in poor health and premature death. C. elegans possess vast orthologous genes associated with PMD, allowing high throughput analysis of the functional consequences of mutant genes. The endogenous gaseous mediator hydrogen sulfide (H2S) is an evolutionary conserved mitochondrial electron source and post-translational regulator across species. Since H2S augments cellular bioenergetics in conditions where mitochondrial dysfunction is a consequence of disease, we investigated whether mitochondria-targeted H2S using novel compounds we have developed (mtH2S) could restore cellular bioenergetics where mitochondrial dysfunction is a direct cause of the disease state (e.g. PMD). Methods: We characterised life/healthspan of 40 C. elegans homologues of human PMD mutations to identify PMD genes associated with poor health using a high-throughput microfluidic device. PMD strains displaying reduced life and/or health were assessed for improved health/longevity in the presence of our novel mtH2S molecules. Strains showing mtH2S -induced improvements were further assessed for ATP production, mitochondrial deltaΨm, oxygen consumption and total sulfide. Results: Seven PMD mutants were characterised with 5 showing reduced survival/locomotion. Of these, 2 strains displayed significant improvement with mtH2SD (100nM). Animals with widespread electron transport chain deficiency (gfm-1 and mrsp-16) were not responsive to mtH2S. abtm-1 mutants showed no improvement in life/healthspan despite significant preservation of mitochondrial deltaΨm on day 2 of adulthood. However, in a complex I mutant (nuo-4; a Leigh syndrome orthologue), mtH2SD significantly reversed the decline in ATP levels, preserved mitochondrial deltaΨm and increased survival/movement. Furthermore, mtH2S compounds significantly increased global sulfide levels in a complex IV mutant (sco-1), preserving mitochondrial deltaΨm and delaying severe movement decline (untreated sco-1: 32% of population active vs 68% in mtH2S sco-1 at day 6). Conclusion: Our data shows for the first time that mtH2S are potent molecules in PMD, effective in the nM range, and present a novel approach to at least delay mitochondrial perturbations in a variety of PMD disorders. Complete characterisation of all known PMD orthologues will significantly contribute to the precise disease mechanisms of PMD and potential therapeutics.