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Fig. 1 Schematic overview of experimental validation of combinatorial therapies in C. elegans and zebrafish models of respiratory chain complex I disease. Having previously identified 37 individual compounds in three major drug classes that significantly improved the short lifespan of complex I-deficient gas-1(fc21) mutant (that has a homozygous missense mutation in the nuclear-encoded complex I structural subunit NDUFS2 orthologue) C. elegans (worms) (Supplementary Material, Fig. S1), 11 combinations were randomly selected to evaluate the efficacy, toxicity and synergy of combining treatment classes on gas-1(fc21) worms’ lifespan as a primary outcome. Mechanistic analyses were performed at the level of mitochondrial physiology, transcriptome and metabolome analyses to interrogate the lead synergistic combination (glucose (Glu) + nicotinic acid (NAC) + N-acetylcysteine (NAC)). Validation of this lead combinatorial therapy was performed to assess brain death, swimming activity and effects on central biochemical readouts of mitochondrial dysfunction in a vertebrate zebrafish model of mitochondrial respiratory chain disease caused by pharmacologic (rotenone) inhibition of complex I function.