Inherited disorders of mitochondrial oxidative phosphorylation can be caused by mutations in at least 290 genes and affect approximately 1 in 5,000 live births, with no proven therapies to date. In a mouse model of Leigh Syndrome harboring a deletion of the Complex I subunit Ndufs4 (LPD-5 in C. elegans), breathing hypoxia extends lifespan and prevents neurodegeneration, while exposure to modest hyperoxia exacerbates the disease and results in rapid death. The precise mechanism underlying the Complex I rescue by hypoxia and sensitivity to hyperoxia remains elusive. Here, we show that Complex I mutants in C. elegans including
lpd-5 and
nduf-7 are similarly rescued by hypoxia and sensitive to mild hyperoxia with respect to growth and development. Genetic activation of HIF-1 is not sufficient to rescue Complex I mutants, nor is HIF-1 necessary for the beneficial effect of hypoxia. To gain further insight into the interaction between Complex I dysfunction and oxygen we used forward genetics to isolate genetic suppressors of
nduf-7 and
gas-1 in hyperoxia. We identified an intra-complex missense mutation in a supernumerary subunit of Complex I, which confers dominant suppression of
nduf-7,
gas-1, and
lpd-5 in hyperoxia. Ongoing studies, including additional forward genetic screens, promise to shed light on the mechanisms underlying the interaction between Complex I and oxygen.