Oxygen consumption by cultured human cells is impaired by a nucleoside analogue cocktail that inhibits mitochondrial DNA synthesis.
We evaluated oxygen consumption rates in human cells cultured in the presence of a nucleoside analog reverse transcriptase inhibitor (NRTI) cocktail that inhibits mitochondrial DNA synthesis. We treated a proliferating human lymphocyte cell line and a primary culture of human adipose cells with antiretroviral drugs (AZT+ddC+d4T). The effects of these drugs on mitochondrial DNA (mtDNA) levels and oxygen consumption rates were evaluated using semi-quantitative real-time PCR and an on-line monitoring Clark electrode system. We found that the NRTI treatment lowered oxygen consumption rates and inhibited mitochondrial DNA replication in human cell cultures. Inhibition of oxygen consumption was linearly proportional to inhibition of mtDNA replication. These results show for the first time that mitochondrial respiration is impaired in NRTI sensitive cells. The linear relationship between NRTI inhibition of respiration and NRTI inhibition of mtDNA replication indicates that small decreases in mtDNA levels can lead to respiratory deficits in the tissues of patients treated with anti-HIV drugs. We propose a model that takes into account the small differences in metabolic dynamics between peripheral and axial/visceral fat tissues. This model explains how NRTI-related respiratory deficits may lead to the presentation of opposing lipodystrophic syndromes in same patient.
Petit
Caroline
C
Département Maladies Infectieuses, Institut Cochin, INSERM U567, CNRS UMR 8104, Université René Descartes, Laboratoire Génétique des Virus, 22 rue Méchain, 75014 Paris, France.
Piétri-Rouxel
France
F
Lesne
Annick
A
Leste-Lasserre
Thierry
T
Mathez
Dominique
D
Naviaux
Robert K
RK
Sonigo
Pierre
P
Bouillaud
Frédéric
F
Leibowitch
Jacques
J
D017667:Adipocytes / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D008954:Models, Biological; D010101:Oxygen Consumption / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology; D016047:Zalcitabine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D004272:DNA, Mitochondrial; D008055:Lipids; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016047:Zalcitabine; D018119:Stavudine