Oxidative mitochondrial DNA damage in peripheral blood mononuclear cells is associated with reduced volumes of hippocampus and subcortical gray matter in chronically HIV-infected patients

Abstract

Cross-sectional relationships were examined between regional brain volumes and mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral blood mononuclear cells (PBMCs) of 47 HIV patients [mean age 51years; 81% with HIV RNA ≤50copies/mL] on combination antiretroviral therapy. The gene-specific DNA damage and repair assay measured mtDNA 8-oxo-dG break frequency. Magnetic resonance imaging was performed at 3T. Higher mtDNA 8-oxo-dG was associated with lateral ventricular enlargement and with decreased volumes of hippocampus, pallidum, and total subcortical gray matter, suggesting the involvement of systemic mitochondrial-specific oxidative stress in chronic HIV-related structural brain changes and cognitive difficulties. Clarification of the mechanism may provide potential therapeutic targets.

Keywords: Atrophy; Brain; Neuroinflammation; Oxidative stress; Pallidum; ROS.

Fig. 1

Data distributions of peripheral blood mononuclear cell mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) (break frequency). Left: full distribution; right: distribution of positive values. For each boxplot, the middle dark line shows the median; the shaded box indicates the 1st (Q1) and 3rd (Q3) quartiles. Whiskers extend the box range to the extreme data points or, if there are outliers, by 1.5×(Q3-Q1) in either direction; circles are outliers (< Q1 − 1.5×[Q3 − Q1] or > Q3 + 1.5×[Q3 − Q1]).

Fig. 2

Top: boxplots showing total volumes of hippocampus for subject groups with zero and positive values of mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral blood mononuclear cells; p = 0.07 by Mann–Whitney test. Bottom: total volumes of hippocampus plotted against mtDNA 8-oxo-dG for entire study population.