LAUSR

Coenzyme Q (CoQ) is a lipid-soluble antioxidant, with the oxidized (ubiquinone) and the reduced (ubiquinol) forms, and also an electron carrier for the electron transport chain. CoQ6 is synthesized by at least nine proteins (Coq1--9), and many of them form the Coq protein complex in the mitochondria in yeast. CoQ is present in the form of CoQ10 in humans. Yeast Coq1 corresponds to PDSS1 and PDSS2 proteins in humans. Mutations in PDSS or COQ genes are associated with primary CoQ10 deficiency. Secondary CoQ10 deficiency is associated with mitochondrial DNA mutation. We have demonstrated that the human COQ5, present as a mature protein without mitochondrial targeting sequence in the mitochondria, is required for maintaining CoQ10 levels. The maturation of COQ5 protein and the stability of the COQ5-containing protein complex in the mitochondria were suppressed by the conditions of mitochondrial energy deficiency. Here we further investigated the roles of COQ3 and COQ7 proteins in maintaining CoQ10 levels and in the mitochondria. Our results showed that both COQ3 and COQ7 were required for maintaining CoQ10 levels in human 143B cells, but the degree of the decrease in CoQ10 levels was greater after COQ7 knockdown than that after COQ3 knockdown. After COQ7 knockdown, but not after COQ3 knockdown, the ubiquinol-10:ubiquinone-10 ratio was increased and the peaks corresponding to the putative substrate of the COQ7 enzyme, 5-demethoxyubiquinone-10 (DMQ10/DMQ10H2), appeared on the HPLC chromatograms. The CoQ10 levels in the mitochondria were also decreased after COQ3 or COQ7 knockdown, and the putative DMQ10 was present in the mitochondria after COQ7 knockdown. Moreover, COQ3 or COQ7 knockdown caused decreased mitochondrial respiratory functions. Only COQ3 knockdown could decrease the stability of PDSS2 and several COQ proteins. Furthermore, mature forms of COQ3 and COQ7 were found in the mitochondria. Levels of the mature COQ7 protein, but not COQ3, were suppressed in 143B cells treated with the chemical uncoupler FCCP and in the cybrids harboring a pathogenic mitochondrial DNA mutation, which both had diminished CoQ10 levels. All these novel findings may further elucidate the functions of COQ proteins and their roles in human diseases.