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Mitochondrial dysfunctions in circulating T lymphocytes from human
immunodeficiency virus-1 carriers [see comments]
A Macho, M Castedo, P Marchetti, JJ Aguilar, D Decaudin, N Zamzami, PM Girard, J Uriel and G Kroemer
CNRS-UPR420, Villejuif, France.
In several models of lymphocyte apoptosis, two alterations of mitochondrial
function precede advanced DNA fragmentation: (1) a reduction of
mitochondrial transmembrane potential (delta psi m) and (2) an increase in
mitochondrial generation of superoxide anion. Here we show that two
fluorochromes allow for the identification of analogous mitochondrial
perturbations in circulating T lymphocytes from human immunodeficiency
virus (HIV)-1+ donors. The first among these fluorochromes, the cationic
lipophilic dye DiOC6(3), measures delta psi m; the second marker,
hydroethidine (HE), is nonfluorescent, unless it is oxidized by superoxide
anions to the product ethidium (Eth). CD4+ or CD8+ cells from clinically
asymptomatic HIV-1 carriers contain a significantly elevated percentage of
cells endowed with enhanced HE --> Eth conversion and/or reduced
DiOC6(3) uptake as compared with normal controls. Phenotypic
characterization of (HE --> Eth)high cells from HIV+ donors shows that
these cells possess a low delta psi m, thus demonstrating a functional
alteration of mitochondria. In addition, (HE --> Eth)high cells display
a reduced incorporation of the cardiolipin- specific dye nonyl-acridine
orange (NAO), showing a structural defect of the cardiolipin-containing
inner mitochondrial membrane. Control experiments involving rotenone, an
inhibitor of the respiratory chain complex I, indicate that the reactive
oxygen species responsible for HE --> Eth conversion is generated during
mitochondrial electron transport. In synthesis, it appears that
mitochondrial alterations occur in a significant percentage of circulating
T lymphocytes from HIV- 1 carriers. The extent of delta psi m reduction, as
determined ex vivo, correlates with the frequency of cells undergoing DNA
fragmentation after overnight in vitro culture. These observations may be
important for the understanding and for the direct ex vivo quantitation of
HIV- triggered lymphocyte destruction.
Volume 86,
Issue 7,
pp. 2481-2487,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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