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Antimicrob. Agents Chemother. doi:10.1128/AAC.01449-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mitochondrial DNA content: an inaccurate biomarker of mitochondrial alteration in HIV-related lipodystrophy

Inserm, U582, Paris, F-75013, France; Université Pierre et Marie Curie (UPMC-Paris 6), Paris, France; Inserm, U680, Paris, F-75012, France; AP-HP, Hôpital Pitié-Salpêtrière, Service de Biochimie, Paris, F-75651 France; AP-HP, Service de Biochimie, and Service de Chirurgie, Hôpital Tenon, Paris, F-75020 France

^* To whom correspondence should be addressed. Email: a.lombes{at}institut-myologie.org.

	Abstract

Lipoatrophy is a prevalent side effect of antiretroviral treatment of HIV infection. Its mechanisms are still disputed but include mitochondrial toxicity, in particular mitochondrial DNA (mtDNA) depletion induced by nucleoside reverse transcriptase inhibitors. To obtain an integrated evaluation of the mitochondrial alteration in lipoatrophy, we investigated its DNA, RNA and protein levels in 15 samples of abdominal subcutaneous adipose tissue from HIV-infected patients with peripheral lipoatrophy and compared them with 15 samples from age- and BMI-matched controls. DNA and RNA analyses used PCR-based techniques while proteins were quantified with ELISA and activity with spectrophotometric assays.

Depletion of mtDNA and mtDNA-encoded MT-CO2 mRNA was present but normal levels of mtDNA-dependent activity (cytochrome c oxidase) and protein (MT-CO2p) showed that it was compensated for. Increase of nuclear DNA-dependent mitochondrial activities (citrate synthase and malate dehydrogenase) and protein (COX4I1p) as well as transcriptional up-regulation of nuclear DNA-encoded mitochondrial genes (COX4I1 and UCP2) demonstrated increased mitochondrial biogenesis. However expression of the known transcription factors of mitochondrial biogenesis (TFAM, NRF1, GABPA, PPARGC1A, PPARGC1B, and PPRC1) was normal or decreased. Increased amount of activated caspase 3 and of DDIT3 mRNA showed the induction of apoptosis and oxidative stress respectively. The mtDNA content did not correlate with any other mitochondrial parameter

In conclusion, mtDNA content does not appear to be an accurate biomarker of mitochondrial alteration in lipoatrophic adipose tissue. Preservation of mtDNA-dependent mitochondrial functions occurred despite severe mtDNA depletion. The presence of significant oxidative stress and apoptosis did not correlate with mtDNA content.