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  • Review Article
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Mitochondrial toxicity of nrti antiviral drugs: an integrated cellular perspective

Nature Reviews Drug Discovery volume 2, pages 812–822 (2003)Cite this article

Key Points

  • Nucleoside reverse transcriptase inhibitors (NRTIs) are linchpins to AIDS therapy, but mitochondrial side effects have increasingly come to light.

  • Mitochondrial DNA (mtDNA) depletion and energy depletion are key observations and relate clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro, but related pharmacological events could be operative as well.

  • Subsequent observations indicated that mitochondrial energy deprivation is concomitant with, or is the result of, mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself.

  • Moreover, mtDNA mutations can become important as NRTI therapy continues.

Abstract

Highly active antiretroviral therapy (HAART) regimes based on nucleoside reverse transcriptase inhibitors (NRTIs) have revolutionized the treatment of AIDS in recent years. Although HAART can successfully suppress viral replication in the long term, it is not without significant toxicity, which can seriously compromise treatment effectiveness. A major toxicity that has been recognized for more than a decade is NRTI-related mitochondrial toxicity, which manifests as serious side effects such as hepatic failure and lactic acidosis. However, a lack of understanding of the mechanisms underlying mitochondrial toxicity has hampered efforts to develop novel drugs with better side-effect profiles. This review characterizes the pharmacological mechanisms and pathways that are involved in mitochondrial dysfunction caused by NRTIs, and suggests opportunities for future pharmacological research.

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Figure 1: Nucleoside reverse transcriptase inhibitors.
Figure 2: Mitochondrial effects of NRTIs.
Figure 3: Modes of inhibition of DNA pol-γ by NRTIs.
Figure 4: DNA pol-γ amino acids involved in nucleotide selection.
Figure 5: Location of non-synonymous single nucleotide polymorphisms in the gene encoding DNA pol-γ and amino-acid changes in the protein.

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Acknowledgements

Supported by DHHS NIH R01 HL59798, HL63666, HL72707, and AA13551 to WL.

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Authors and Affiliations

  1. Department of Pathology, Emory University, 1639 Pierce Drive, Room 7117, Atlanta, 30322, Georgia, USA

    William Lewis

  2. Department of Medicine, National Jewish Medical & Research Center, 1400 Jackson Street, Goodman Building, Room 715, Denver, 80206, Colorado, USA

    Brian J. Day

  3. National Institute of Environmental Health Sciences, Laboratory of Molecular Genetics, PO Box 12233, Research Triangle Park, North Carolina, 27709, USA

    William C. Copeland

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DATABASES

LocusLink

DNA pol-α

DNA pol-δ

DNA pol-ε

DNA pol-γ

HIV-1 reverse transcriptase

TK1

TK2

Online Mendelian Inheritance in Man

Alper's syndrome

congestive heart failure

mtDNA depletion syndromes

PEO

Glossary

MITOCHONDRIA

Mitochondria generate cellular energy in the form of ATP by the process of oxidative phosphorylation. Mammalian mitochondrial DNA contains 13 genes that code for proteins, all of which are essential for oxidative phosphorylation.

ADP/ATP TRANSLOCATOR

The protein that transports ADP and ATP across the mitochondrial membrane.

OXIDATIVE PHOSPHORYLATION

The production of ATP from ADP using the electrochemical gradient established by the mitochondrial electron transport chain. The proteins involved in oxidative phosphorylation are located within the mitochondrial inner membrane, and include the ADP/ATP translocator, the electron-transport-chain complexes I, II, III and IV and ATP synthase.

S-PHASE

The phase of the eukaryotic cell cycle in which DNA is synthesized.

MITOCHONDRIAL SALVAGE PATHWAY

The enzymatic pathway available to maintain the pool of intramitochondrial nucleosides.

FIDELITY OF REPLICATION

The accuracy with which DNA polymerase copies DNA.

KEARNS-SAYRE SYNDROME

A combination of progressive external opthalmoplegia, cardiac conduction defects and progressive hearing loss, usually due to large mtDNA deletions.

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Lewis, W., Day, B. & Copeland, W. Mitochondrial toxicity of nrti antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov 2, 812–822 (2003). https://doi.org/10.1038/nrd1201

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