In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA

National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, NSW 2010, Australia.
The Journal of Infectious Diseases (Impact Factor: 6). 06/2005; 191(10):1686-96. DOI: 10.1086/429697
Source: PubMed


Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described.
We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks.
We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues.
Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.

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    • "A study has demonstrated increased plasma mtDNA in acute HIV seroconverters and ART-naive subjects compared with HIV-seronegative controls and long-term nonprogressors, and a positive correlation between plasma HIV RNA and plasma mtDNA was also observed [36]. However, it is worth mentioning that both increases and decreases in mtDNA have been reported in pathogenic conditions as there is not a standard tool for defining what constitutes an abnormal mtDNA quantity, and therefore, data from heterogeneous HIV-infected populations were inconsistent [37] [38] [39] [40] [41]. "
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    ABSTRACT: Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the “Pol- γ hypothesis.” HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.
    Oxidative Medicine and Cellular Longevity 07/2013; 2013(12, article 1109):493413. DOI:10.1155/2013/493413 · 3.36 Impact Factor
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    • "Not every case of mtDNA depletion leads to changed expression levels or activity of mitochondrial respiratory chain proteins (Stankov et al., 2010). In addition, altered mitochondrial gene expression and impaired respiratory chain activity have been observed without mtDNA depletion (Mallon et al., 2005; Viengchareun et al., 2007). Expression profiles of mitochondrial mRNA possibly explain these occurrences as they have been shown to adjust, both in a peripheral blood mononuclear cell line and mice upon exposure to NRTIs. "
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    ABSTRACT: Highly Active Anti-Retroviral Therapy (HAART) has significantly increased life expectancy of the HIV-positive population. Nevertheless, the average lifespan of HIV patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for this difference invokes heavily on viral stimulus despite HAART efficiency in viral suppression. We propose here that the premature and accelerated ageing of HIV patients can also be caused by adverse effects of antiretroviral drugs, specifically those that affect the mitochondria. The Nucleoside Reverse Transcriptase Inhibitor (NRTI) antiretroviral drug class for instance, is known to cause depletion of mitochondrial DNA via inhibition of the mitochondrial specific DNA polymerase-. Besides NRTIs, other antiretroviral drug classes such as Protease Inhibitors also cause severe mitochondrial damage by increasing oxidative stress and diminishing mitochondrial function. We also discuss important areas for future research and argue in favour of the use of C. elegans as a novel model system for studying these effects.
    Frontiers in Genetics 01/2013; 3. DOI:10.3389/fgene.2012.00328
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    • "However, these drugs have side effects such as lipodystrophy, neuropathy, myopathy, and liver steatosis, all of which are related to mitochondrial toxicity. In vitro and in vivo studies have shown that some NRTIs inhibit DNA polymerase-γ, a nuclear-encoded polymerase important for mitochondrial DNA (mtDNA) replication [3,4]. Depletion of mtDNA induced by NRTIs may attenuate mitochondrial oxidative phosphorylation, which could limit their clinical use. "
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    ABSTRACT: Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal β-cell line, INS-1E. The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed. Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 μM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction. Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.
    BMC Gastroenterology 01/2012; 12(1):4. DOI:10.1186/1471-230X-12-4 · 2.37 Impact Factor
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