Mitochondrial deoxyribonucleotide pools in deoxyguanosine kinase deficiency.

Mutated deoxyguanosine kinase (dGK), which catalyses the first step of the mitochondrial deoxypurine salvage pathway, accounts for a hepatocerebral variant of mitochondrial DNA (mtDNA) depletion syndromes. In order to elucidate the pathogenic mechanism of dGK deficiency, mitochondrial and cytoplasmic deoxyribonucleoside triphosphate (dNTP) pools in cycling and quiescent fibroblasts from a dGK deficient patient were measured. The mitochondrial dNTP pools were found to be imbalanced, mainly in quiescent cells due to decreased dGTP while mtDNA content and mitochondrial respiratory chain activities were concomitantly decreased. Supplementation of deoxyguanosine and deoxyadenosine normalized mitochondrial dNTP pools, mtDNA content and partially restored the MRC function. It is suggested that the cytoplasmic deoxycytine kinase supplemented with external substrates may compensate for the deficient dGK.