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

Kaleb C. Lund, Kendall B Wallace

Research output: Contribution to journalReview article

31 Scopus citations

Abstract

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-γ (poly-γ), 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 poly-γ 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 poly-γ. 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.

Original languageEnglish (US)
Pages (from-to)217-228
Number of pages12
JournalCardiovascular Toxicology
Volume4
Issue number3
DOIs
StatePublished - Oct 29 2004

Keywords

  • AIDS
  • Bioenergetics
  • DNA pol-γ
  • HAART
  • In vitro
  • Mitochondria
  • NRTI

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