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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    • "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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    • "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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