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. Consequently, mitochondria are particularly susceptible to inhibition of DNA replication by the NRTIs, which is consistent with the phenotype of mitochondrial depletion and metabolic failure in affected patients. However, the DNA pol-gamma hypothesis by itself fails to explain the entire array of metabolic deficiencies associated with NRTI-induced disorders. In this article, we review the published literature regarding the direct effects of NRTIs on various mitochondrial targets and suggest the possibility that the initiating event in NRTI-induced cardiomyopathy is a direct mitochondrial toxicity rather than inhibition of mitochondrial DNA pol-gamma. The goal of this review is to encourage a discussion of the cause of NRTI-induced mitochondrial cardiomyopathy to include a fresh consideration of all possible targets and integrating pathways that are involved in establishing mitochondrial bioenergetic fidelity and metabolic capacity in the affected myocardium.
Department of Biochemistry and Molecular Biology, Toxicology Graduate Program, University of Minnesota School of Medicine, Duluth, MN 55812-3031, USA. klund2@d.umn.edu
Kaleb C
KC
Lund
Kendall B
KB
Wallace
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009705:Nucleosides / Q000009:adverse effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D013385:Succinate Dehydrogenase / Q000378:metabolism
D006420:Hemeproteins; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D013385:Succinate Dehydrogenase; D009245:NADH Dehydrogenase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D006180:Proton-Translocating ATPases; D014450:Electron Transport Complex III