Human HepG2 cells were cultured in NARTI Zalcitabine (ddC) for 6 days to ensure a significant effect on mitochondrial DNA replication. The drug reduced mitochondrial DNA levels and hence mitochondrial protein expression. As a consequence the assembly of Complexes I, III and IV were severely affected. Note that loss of the two small mitochondrial DNA encoded subunits of Complex V (ATP synthase) does not affect overall assembly. Interestingly an increase in Complex II was induced as a consequence of I, III, IV loss possibly to up regulate mitochondrial citric acid cycle function.