Mitochondrial toxicity of antiviral drugs

Lewis, William; Dalakas, Marinos C.

doi:10.1038/nm0595-417

Cited by 726 publications

(469 citation statements)

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“…NRTIs are firmly linked to altered mtDNA replication 10,37,38 through the DNA pol g hypothesis. 39 This was expanded to include oxidative stress and mtDNA mutations in a 'mitochondrial dysfunction hypothesis' 4,40 where the importance of intramitochondrial availability of NRTIs and other features were increasingly apparent. Data herein in vivo underscore points of the hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Lewis

Haase

Miller

et al. 2005

Laboratory Investigation

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Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3 0 azido-3 0 -deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs. Keywords: deoxynucleotide; NRTI; AIDS; antiretroviral; mitochondrial import; DNC; cardiac; HIV The inner mitochondrial membrane contains transport proteins to move molecules into and out of the matrix. Members of the mitochondrial carrier family of proteins contain three conserved tandemrepeated sequences (B100 residues with two hydrophobic transmembrane a-helices and a hydrophilic segment thought to be an extramembranous loop 1 ). One of these proteins functions as a deoxynucleotide carrier (DNC) to import phosphorylated precursors of mitochondrial (mt-) DNA synthesis and has been characterized. 1-3 Toxicity to mitochondria from antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) is an established side effect of AIDS therapy that limits effective treatment (reviewed in Lewis et al 4 ). Alternative combinations that are NRTI-sparing may be effective if toxicity is a significant clinical problem (reviewed in Joly et al 5 ).Since DNC provides a route for mitochondrial uptake of NRTIs including zidovudine (3 0 azido-3 0 -deoxythymidine or AZT) and stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T), its role in mitochondrial NRTI import and toxicity was addressed in vivo using transgenic mice (TG) and HAART treatment. One HAART regimen included NRTIs (with either an AZT or D4T 'backbone'). A second NRTI-sparing regimen was administered in parallel as a control.DNC ov...

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Section: Discussionmentioning

confidence: 99%

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Lewis

Haase

Miller

et al. 2005

Laboratory Investigation

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“…Elevated plasma lactate now is seen commonly with combined antiretroviral therapy (HAART) (Carr et al, 1999;Moyle, 2000). Mitochondrial toxicity of NRTIs was established by previous investigations (Brinkman et al, 1998;Kakuda et al, 1999;Lewis, 1998;Lewis et al, 1991Lewis et al, , 1992Lewis and Dalakas, 1995;Swartz, 1995), but the clinical impact of NRTI toxicity in patients with AIDS remains controversial. Long-term side effects of NRTIs may be more common because of increased AIDS survival.…”

Section: Mitochondrial Dysfunction Hypothesismentioning

confidence: 99%

“…The accessory subunit provides tighter DNA binding of the complex, thus allowing highly processive DNA synthesis . Dalakas et al, 1990Arnaudo et al, 1991Chattha et al, 1993d'Amati et al, 1992Freiman et al, 1993Herskowitz et al, 1992Jolliet and Widmann, 1990 Kohler and Lewis, 1998Lewis and Dalakas, 1995Lewis et al, 2000Lipshultz et al, 2000Sinnwell et al, 1995 Decreased mtDNA in vitro. Decreased mtDNA, mtRNA, mitochondrial polypeptides, and mitochondrial ultrastructural damage in vivo.…”

Section: Mtdna Dna Polymerase-␥ and Nrti Toxicitymentioning

confidence: 99%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

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“…Mitochondrial‐derived clinical effects of NRTI have been firmly established in HIV‐infected non‐pregnant adults 18, 19, 20. These negative effects depend on the capacity of NRTIs to inhibit DNA polymerase gamma, the enzyme devoted to mitochondrial DNA (mtDNA) replication, leading to a decrease in mtDNA copy number and quality, which may, finally, cause mitochondrial dysfunction 18. Depletion of mtDNA has been extensively described in different tissues of human and animal models (placenta, foetal cord blood, heart, adipose tissue, skeletal muscle, brain and kidney, among others) leading to mitochondrial morphologic, metabolic and energetic abnormalities 21, 22, 23, 24, 25.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial toxicity and caspase activation in HIV pregnant women

Hernández

Morén

Catalán-García

et al. 2016

J Cellular Molecular Medi

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To assess the impact of HIV‐infection and highly active anti‐retroviral treatment in mitochondria and apoptotic activation of caspases during pregnancy and their association with adverse perinatal outcome. Changes of mitochondrial parameters and apoptotic caspase activation in maternal peripheral blood mononuclear cells were compared at first trimester of pregnancy and delivery in 27 HIV‐infected and ‐treated pregnant women versus 24 uninfected pregnant controls. We correlated immunovirological, therapeutic and perinatal outcome with experimental findings: mitochondrial DNA (mtDNA) content, mitochondrial protein synthesis, mitochondrial function and apoptotic caspase activation. The HIV pregnancies showed increased adverse perinatal outcome (OR: 4.81 [1.14–20.16]; P < 0.05) and decreased mtDNA content (42.66 ± 5.94%, P < 0.01) compared to controls, even higher in naïve participants. This depletion caused a correlated decrease in mitochondrial protein synthesis (12.82 ± 5.73%, P < 0.01) and function (20.50 ± 10.14%, P < 0.001), not observed in controls. Along pregnancy, apoptotic caspase‐3 activation increased 63.64 ± 45.45% in controls (P < 0.001) and 100.00 ± 47.37% in HIV‐pregnancies (P < 0.001), in correlation with longer exposure to nucleoside analogues. HIV‐infected women showed increased obstetric problems and declined genetic and functional mitochondrial parameters during pregnancy, especially those firstly exposed to anti‐retrovirals. The apoptotic activation of caspases along pregnancy is emphasized in HIV pregnancies promoted by nucleoside analogues. However, we could not demonstrate direct mitochondrial or apoptotic implication in adverse obstetric outcome probably because of the reduced sample size.

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Mitochondrial toxicity of antiviral drugs

Cited by 726 publications

References 51 publications

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Mitochondrial toxicity and caspase activation in HIV pregnant women

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