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: 5.78). 06/2005; 191(10):1686-96. DOI: 10.1086/429697
Source: PubMed

ABSTRACT 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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    • "Numerous mechanisms have been proposed to explain the deleterious impact of NRTIs including mitochondrial depletion, impaired mitochondrial replication via inhibition of the mitochondrial DNA polymerase gamma (POLγ), and subsequent increase in reactive oxygen species (ROS; Lewis et al. 2003). POLγ-independent mechanisms of impairing mitochondrial function have also been implicated, including decreased mitochondrial DNA transcription and altered expression of lipid metabolism genes (Mallon et al. 2005). Mitochondrial dysfunction is a feature of a number of neurodegenerative diseases including AD, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease (Knott et al. 2008; Lin and Beal 2006). "
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    • "On the other hand, there have been suggestions that antiretroviral treatment causes lipodystrophy only when acting upon HIV-1-infected patients, and that events related to HIV-1 infection are intrinsically associated with the development of the syndrome. Evidently, there are no data on long-term antiretroviral treatment of non-HIV-1- infected patients that could establish the specific role of HAART independent of the HIV-1 infection, and a single two-week study of nucleotide-analog reverse transcriptase inhibitor treatment of non-infected volunteers indicated the appearance of only a few features of the lipodystrophy syndrome [7]. Some data have indicated that mild alterations of adipose tissue biology are already present in nontreated HIV-1- infected patients [8]. "
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