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

Lewis, William; Copeland, William C.; Day, Brian J.

doi:10.1038/labinvest.3780288

Cited by 156 publications

(114 citation statements)

References 141 publications

(169 reference statements)

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“…Using a transgenic AIDS model and an approach that resembled those recently used (Lewis, 2001a(Lewis, , 2001bLewis et al, 2001a;Raidel et al, 2002) by our group, this study addressed the contribution of HIV-1 (as expressed in a transgenic HIV-1 construct) and cocaine to the development of CM in AIDS and conversely the impact of AIDS on cocaine cardiotoxicity. Our results indicate that cocaine and HIV-1 together impact on LV mass, and the presence of both conditions impairs cardiac function and accelerates mortality compared with either parameter alone.…”

Section: Discussionmentioning

confidence: 99%

Cocaine Increases Mortality and Cardiac Mass in a Murine Transgenic Model of Acquired Immune Deficiency Syndrome

Sutliff

Haase

Russ

et al. 2003

Laboratory Investigation

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SUMMARY:Cardiac dysfunction in AIDS is an important problem. Cocaine is an epidemic associated with sudden death, cardiac dysfunction, and congestive heart failure. Cocaine use and HIV infection frequently coexist in the same patient, yet the combined impact of both is poorly understood. The present study uses cocaine treatment of an established murine AIDS transgenic model (NL4-3⌬ gag/pol; TG) to define the combined effects of AIDS and cocaine on cardiac pathophysiology. To determine the effects of cocaine and HIV-1 proteins on mortality, wild-type and NL4-3⌬ gag/pol mice received saline or cocaine via continuous infusion by Alzet osmotic pumps for 28 days (chronic). Acute cocaine administration (10 days; 40 mg/kg/day) was used to study the nonlethal effects of cocaine in TGs. Echocardiograms and single time point electrocardiograms were performed at the termination of each experiment. Hearts were removed and examined histopathologically. Chronic cocaine treatment (80 mg/kg/day; 28 days) markedly decreased median survival in both wild-type and TG; however, TG survival was significantly more decreased. In acute studies, TG echocardiographic changes included increased left ventricular mass and increased left ventricular fractional shortening compared with all cohorts. Electrocardiographic changes were absent among the groups. Histopathologically, perivascular fibrosis and interstitial fibrosis were evident in cocaine-treated TG. Data suggest that additive cardiac insults (from AIDS and cocaine) result in combined deleterious effects. (Lab Invest 2003, 83:983-989). C ocaine may contribute to the development of cardiomyopathy (CM) in AIDS as a toxin to myocardial cells or through indirect mechanisms based on cocaine's vascular effects and secondary myocardial changes. Accordingly, cardiac effects of cocaine may be a comorbid condition in AIDS CM and vice versa.Cocaine is rapidly cleared and distributed to heart, brain, spinal cord, and other tissues (Inaba et al, 1978;Som et al, 1994;Volkow et al, 1992). Excellent data regarding CM in chronic cocaine administration in humans comes from heart transplantation studies (Karch and Billingham, 1988). Morphologic features in native hearts from chronic cocaine abusers who underwent heart transplantation differed from those seen in non-cocaine abusers.The purpose of our experiments was to address the individual, additive, or synergistic deleterious effects of cocaine and AIDS on the development of cardiac structural and functional abnormalities. We used an established AIDS transgenic model [NL4-3⌬ gag/pol (TG); reviewed in Klotman and Notkins, 1996] that we have used in the past to study CM in AIDS . Mice received continuous cocaine infusion via miniosmotic pumps for 10 days (acute) and 28 days (chronic). Treatment with high-dose cocaine decreased survival in chronic studies. Cocaine-treated TGs develop pathologic lesions including vascular and interstitial fibrosis. Functionally, left ventricular (LV) mass and LV fractional shortening increased in TGs treated with cocaine....

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Section: Discussionmentioning

confidence: 99%

Cocaine Increases Mortality and Cardiac Mass in a Murine Transgenic Model of Acquired Immune Deficiency Syndrome

Sutliff

Haase

Russ

et al. 2003

Laboratory Investigation

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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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“…5 There were also significantly decreased levels of mitochondrial DNA in the muscle and liver tissues of these patients. 4,6,7 These untoward effects are due in part to the inhibition of mitochondrial DNA polymerase-g by NRTIs. 8,9 Additional toxicities associated with NRTIs include peripheral neuropathy (PN), lipoatrophy, hepatic steatosis and lactic acidosis.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

et al. 2007

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Peripheral neuropathy (PN) due to mitochondrial injury complicates HIV therapy with some nucleoside reverse transcriptase inhibitors (NRTIs). Variation in the mitochondrial genome may influence susceptibility to NRTI toxicities. Two non-synonymous mitochondrial DNA polymorphisms, MTND1*LHON4216C (4216C) and MTND2*LHON4917G (4917G) were characterized in HIV-infected participants exposed to NRTIs in a randomized clinical trial. Among 250 self-identified white, non-Hispanic participants, symptomatic PN (X grade 1) developed in 70 (28%). Both 4216C (odds ratio (OR) ¼ 1.98 (95% confidence interval (CI) 1.05-3.75); P ¼ 0.04) and 4917G (OR ¼ 2.93 (95% CI 1.25-6.89); P ¼ 0.01) were more frequent in PN cases. These two polymorphisms remained independently associated with PN after adjusting for age, baseline CD4 count, plasma HIV RNA level, and NRTI randomization arm; 4216C (OR ¼ 2.0 (95% CI 1.1-4.0) P ¼ 0.04) and 4917G (OR ¼ 5.5 (95% CI 1.6-18.7) Po0.01). When 4917G individuals were excluded from the analysis, the association with 4216C was no longer seen. The mitochondrial 4917G polymorphism may increase susceptibility to NRTI-associated PN.

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

Cited by 156 publications

References 141 publications

Cocaine Increases Mortality and Cardiac Mass in a Murine Transgenic Model of Acquired Immune Deficiency Syndrome

Cocaine Increases Mortality and Cardiac Mass in a Murine Transgenic Model of Acquired Immune Deficiency Syndrome

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

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

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