Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions

doi:10.1016/S0166-3542(03)00069-X

Antiviral Research

Volume 58, Issue 3, May 2003, Pages 189-197

https://doi.org/10.1016/S0166-3542(03)00069-X Get rights and content

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are critical in current AIDS therapy, but mitochondrial side effects have come to light with the increased use of these compounds. Clinical experience, pharmacological, cell and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in specific target tissues are observed. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself. With increased use of NRTIs, mtDNA mutations may become increasingly important pathophysiologically. One important future goal is to prevent or attenuate the side effects so that improved efficacy is achieved.

Introduction

Basic and clinically oriented reviews exist in the literature that focus attention on mitochondrial (mt) DNA replication and related events in nucleoside reverse transcriptase inhibitors (NRTI) toxicity in AIDS therapy (Brinkman, 2001; Brinkman et al., 1998, Brinkman et al., 1999, Brinkman et al., 2000; Casademont et al., 2002, Honkoop et al., 1997, Johnson et al., 2001, Kakuda, 2000, Kakuda et al., 1999; Lewis, 2003a, Lewis, 2003b; Lewis, 2000, Lewis et al., 2001, Lewis et al., 2001, Lewis and Dalakas, 1995, Moyle, 2000, Walker, 2001, Wright and Brown, 1990). Despite intense interest and significant knowledge that relates some of pathophysiological mechanisms of mitochondrial toxicity from NRTIs, a number of questions remain to be answered clinically and experimentally. These questions include:

•
What can we predict clinically from in vitro studies about NRTI mitochondrial toxicity?
•
What is the clinical impact of mtDNA depletion in AIDS?
•
Is there a way to treat or prevent or treat NRTI mitochondrial toxicity?
•
Does NRTI toxicity have tissue specificity?

This brief review highlights clinical and basic evidence for NRTI mitochondrial toxicity. Furthermore, it relates known pathophysiological events to the clinical events.

Section snippets

mtDNA replication and DNA polymerase-γ

Nuclear DNA encodes the majority of the oxidative phosphorylation genes (OXPHOS; the principal source of myocardial energy). However, 13 OXPHOS genes are encoded by mtDNA (reviewed in (Wallace, 1992a)). Defects in expression or function of mitochondrially encoded polypeptides become the foundation for the field of mitochondrial genetic diseases (Luft, 1994), and point a way to examine complex diseases (Wallace, 1999). Acquired defects in mtDNA replication occur as secondary effects of defective

Mitochondrial dysfunction, DNA pol-γ hypothesis and NRTIs

The “mitochondrial dysfunction hypothesis” (Lewis et al., 2001, Lewis et al., 2001) is an expansion of our earlier work (Lewis and Dalakas, 1995) articulated as the “DNA pol-γ hypothesis” and the work of other investigators (Wright and Brown, 1990, Parker and Cheng, 1994). The “DNA pol-γ hypothesis” (Lewis and Dalakas, 1995), oxidative stress, and acquired mtDNA mutations are incorporated into a pathophysiological continuum related to energy depletion. Acquired mitochondrial diseases from NRTI

Oxidative stress as a pivotal event in NRTI toxicity

Energy depletion from altered mtDNA replication in NRTI toxicity is a logical consequence (Lewis and Dalakas, 1995; Lewis et al., 1991, Lewis et al., 1994a, Lewis et al., 1994b, Lewis et al., 1992, Lewis et al., 1996, Lewis et al., 1997, Lewis et al., 2000, Lewis et al., 2001, Lewis et al., 2001). However, the effects of oxidative stress may amplify some of the pathophysiological and phenotypic events in NRTI toxicity to mitochondria. Oxidative stress (operationally defined here as an imbalance

Mutations of mtDNA

Hepatic mtDNA from rat exhibits two orders of magnitude greater oxidative DNA damage than does hepatic nuclear DNA. Differences in oxidative damage between nuclear DNA and mtDNA may relate to (1) lack of known repair enzymes for mtDNA error excision; (2) a lack of histones protecting mtDNA; and (3) a subcellular proximity of mtDNA to these oxidants. Exposure of DNA to superoxide-generating systems causes extensive strand breakage and degradation of deoxyribose (Brawn and Fridovich, 1981).

Mitochondrial dysfunction and mtDNA depletion: relationship to nucleoside reverse transcriptase inhibitor (NRTI) pharmacology and biochemistry

Organellar toxicity of mitochondria as an important side effect of NRTI therapy in AIDS is linked pathophysiologically to clinical and experimental settings. Early observations were based in vitro (Chen and Cheng, 1989), animal experiments confirmed those findings in vivo (Lewis et al., 1991, Lewis et al., 1992, Lamperth et al., 1991) clinical correlations were found in AIDS patients (Arnaudo et al., 1991, Dalakas et al., 2001). Cornerstones of the pathogenesis of mitochondrial toxicity from

Can NRTI agents be categorized in a toxicologically meaningful way?

NRTIs have been divided into classes of mtDNA replication inhibitors according to the relative importance of DNA chain termination, or internalization of the analog into nascent mtDNA and substitution for the natural base (Kakuda, 2000, Wright and Brown, 1990, Parker and Cheng, 1994). One class inhibits mtDNA replication in ways include monophosphate incorporation into mtDNA. With these agents, competition with the native nucleotide and NRTI at the nucleotide binding site of DNA pol-γ appears

What is the clinical impact of NRTI mitochondrial toxicity?

With high dose monotherapy, AZT causes a cummulative mitochondrial skeletal myopathy in adult AIDS patients (Dalakas et al., 1990). It is a bona fide complication, (Groopman, 1990, Till and MacDonell, 1990) with characteristic microscopic “ragged red fibers” (Shoubridge, 1994) and ultrastructural paracrystalline inclusions (Dalakas et al., 1990) that result from subsarcolemmal accumulation of mitochondria in the skeletal muscle with long term, high dose treatment in adult AIDS patients.

Summary

NRTI toxicity to mitochondria in different tissues now is an important clinical problem with longterm significance to AIDS patients. Mechanisms likely relate to energy depletion, oxidative stress, and mtDNA mutations. Analogous to treatment of other serious infectious agents, combinations of multiple anti-HIV-1 drugs are used to target different viral proteins or points in virus-host life cycle (Lange, 1995, De Clercq, 1997) and may create combined toxicities to mitochondria. As current

Acknowledgements

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

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ReviewMitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions

Abstract

Introduction

Section snippets

mtDNA replication and DNA polymerase-γ

Mitochondrial dysfunction, DNA pol-γ hypothesis and NRTIs

Oxidative stress as a pivotal event in NRTI toxicity

Mutations of mtDNA

Mitochondrial dysfunction and mtDNA depletion: relationship to nucleoside reverse transcriptase inhibitor (NRTI) pharmacology and biochemistry

Can NRTI agents be categorized in a toxicologically meaningful way?

What is the clinical impact of NRTI mitochondrial toxicity?

Summary

Acknowledgements

Lancet

Metabolism

Arch. Biochem. Biophys.

Lancet

Neuromuscul. Disord.

J. Biol. Chem.

Exp. Gerontol.

Lab. Invest.

Cardiovascular Pathology

J. Pediatr.

Methods Enzymol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Genet.

Am. Heart. J.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Lancet

Clin. Ther.

Prog. Cardiovasc Dis.

Prog. Cardiovasc. Dis.

Lab. Invest.

Lab Invest.

Lab. Invest.

J. Biol. Chem.

J. Biol. Chem.

Mutat. Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Hum. Pathol.

Oxidants, antioxidants, and the degenerative diseases of aging

Proc. Natl. Acad. Sci. U.S.A.

Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity

Lab. Invest.

2′,3′-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients

Neurology

Chick-embryo DNA polymerase gamma. Identity of gamma-polymerases purified from nuclei and mitochondria

Eur. J. Biochem.

Evidence for mitochondrial toxicity: lactic acidosis as proof of concept

J. HIV Ther.

Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway (editorial)

AIDS

Treatment of nucleoside reverse transcriptase inhibitor-induced lactic acidosis

AIDS

The accessory subunit of Xenopus laevis mitochondrial DNA polymerase gamma increases processivity of the catalytic subunit of human DNA polymerase gamma and is related to class II aminoacyl-tRNA synthetases

Mol. Cell. Biol.

Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy

Arthritis Rheum.

Lactic acidosis complicating the acquired immunodeficiency syndrome (see comments)

Ann. Intern. Med.

Once-daily administration of 2′,3′-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial (see comments)

N. Engl. J. Med.

Peripheral neuropathy and antiretroviral drugs

J. Peripher. Nerv. Syst.

Mitochondrial myopathy caused by long-term zidovudine therapy (see comments)

N. Engl. J. Med.

Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage (see comments)

Ann. Neurol.

Review
Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions