Homozygous mice carrying kd (kidney disease) mutations in the gene encoding prenyldiphosphate synthase subunit 2 (Pdss2^kd/kd) develop interstitial nephritis and eventually die from end-stage renal disease. The PDSS2 polypeptide in concert with PDSS1 synthesizes the polyisoprenyl tail of coenzyme Q (Q or ubiquinone), a lipid quinone required for mitochondrial respiratory electron transport. We show that a deficiency in Q content is evident in Pdss2^kd/kd mouse kidney lipid extracts by 40 days of age, and thus precedes the onset of proteinuria and kidney disease by several weeks. The presence of the kd (V117M) mutation in PDSS2 does not prevent its association with PDSS1. However heterologous expression of the kd mutant form of PDSS2 together with PDSS1 in E. coli recapitulates the Q deficiency observed in the Pdss2^kd/kd mouse. Dietary supplementation with Q10 provides a dramatic rescue of both proteinuria and interstitial nephritis in the Pdss2^kd/kd mutant mice. The results presented suggest that Q may be acting as a potent lipid soluble antioxidant, rather than by boosting kidney mitochondrial respiration. Such Q₁₀ supplementation may have profound and beneficial effects in treatment of certain forms of focal segmental glomerulosclerosis that mirror the renal disease of the Pdss2^kd/kd mouse.