Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR),
the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that
lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide
oxidation, proportional to the residual levels of CoQ. Biochemical and
molecular abnormalities are rescued by CoQ supplementation in vitro and
recapitulated by pharmacological inhibition of CoQ biosynthesis in skin
fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2kd/kd mice,
which only have ~15% residual CoQ concentrations and are clinically affected,
showed (i) reduced protein levels of SQR and downstream enzymes, (ii)
accumulation of hydrogen sulfides, and (iii) glutathione depletion. These
abnormalities were not present in brain, which maintains ~30% residual CoQ and
is clinically unaffected. In Pdss2kd/kd mice, we also observed low levels of
plasma and urine thiosulfate and increased blood C4‐C6 acylcarnitines. We
propose that impairment of the sulfide oxidation pathway induced by decreased
levels of CoQ causes accumulation of sulfides and consequent inhibition of
short‐chain acyl‐CoA dehydrogenase and glutathione depletion, which
contributes to increased oxidative stress and kidney failure