Adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors.

Nucleoside analog reverse transcriptase inhibitors (NRTIs) are known to directly inhibit mitochondrial complex I activity as well as various mitochondrial kinases. Recent observations that complex I activity and superoxide production are modulated through cAMP-dependent phosphorylation suggests a mechanism through which NRTIs may affect mitochondrial respiration via kinase-dependent protein phosphorylation. In the current study, we examine the potential for NRTIs to inhibit the cAMP-dependent phosphorylation of complex I and the associated NADH:CoQ oxidoreductase activities and rates of superoxide production using HepG2 cells.

Absence of a universal mechanism of mitochondrial toxicity by nucleoside analogs.

Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 microM; 2.7 and 13.

Direct effects of nucleoside reverse transcriptase inhibitors on rat cardiac mitochondrial bioenergetics.

In this investigation we demonstrate that various nucleoside reverse transcriptase inhibitors (NRTIs) and their corresponding nucleotides can cause a direct, DNA polymerase-gamma-independent, inhibition of respiration, membrane potential, and calcium loading capacity in isolated rat heart mitochondria in vitro. Both AZT and d4T also increased total adenine phosphate energy charge in H9c2 rat cardiac myocytes in cell culture. These results demonstrate that the various NRTI nucleosides and nucleotides are capable, at sufficiently high concentrations, of directly affecting mitochondrial bioenergetics in vitro, which may enhance the toxicity observed in vivo previously attributed to inhibition of DNA polymerase-gamma.

Direct, DNA pol-gamma-independent effects of nucleoside reverse transcriptase inhibitors on mitochondrial bioenergetics.

Nucleoside reverse transcriptase inhibitor (NRTI)-induced cardiomyopathy has been suggested to reflect mitochondrial targets of drug toxicity. The prevailing hypothesis is that, through structural mimicry, the NRTIs are mistaken as substrates for DNA polymerase and incorporated into replicating DNA, where they cause truncation of the elongating strand. Although there exist five forms of nuclear DNA polymerase, mitochondria possess solely DNA polymerase-gamma (pol-gamma), which is a preferred target for most NRTIs.