Primary human CoQ 10 deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for CoQ 10 biosynthesis. Our in vitro studies of PDSS2 mutant fibroblasts, with< 20% CoQ 10 of control cells, revealed reduced activity of CoQ 10-dependent complex II+ III and ATP synthesis, without amplification of reactive oxygen species (ROS), markers of oxidative damage, or antioxidant defenses. In contrast, COQ2 and ADCK3 mutant fibroblasts, with 30–50% CoQ 10 of controls, showed milder bioenergetic defects but significantly increased ROS and oxidation of lipids and proteins. We hypothesized that absence of oxidative stress markers and cell death in PDSS2 mutant fibroblasts were due to the extreme severity of CoQ 10 deficiency. Here, we have investigated in vivo effects of Pdss2 deficiency in affected and unaffected organs of CBA/Pdss2 kd/kd mice at presymptomatic, phenotypic-onset, and end-stages of the disease. Although Pdss2 mutant mice manifest widespread CoQ 9 deficiency and mitochondrial respiratory chain abnormalities, only affected organs show increased ROS production, oxidative stress, mitochondrial DNA depletion, and reduced citrate synthase activity, an index of mitochondrial mass. Our data indicate that kidney-specific loss of mitochondria triggered by oxidative stress may be the cause of renal failure in Pdss2 kd/kd mice.—Quinzii, CM, Garone, C., Emmanuele, V., Tadesse, S., Krishna, S., Dorado, B., Hirano, M. Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice.