Study of oxidative, enzymatic mitochondrial respiratory chain function and apoptosis in perinatally HIV-infected pediatric patients

Abstract

Mitochondrial toxicity in perinatally human immunodeficiency virus (HIV)-infected pediatric patients has been scarcely investigated. Limited data are available about HIV or antiretroviral (ARV)-mediated mitochondrial damage in this population group, specifically, regarding oxygen consumption and apoptosis approach. We aimed to elucidate whether a given mitochondrial DNA depletion is reflected at downstream levels, to gain insight on the pathology of HIV and highly active antiretroviral therapy (HAART) in perinatally HIV-infected pediatric patients. We studied 10 healthy control participants and 20 perinatally HIV-infected pediatric patients (10 under ARV treatment and 10 off treatment). We determined mitochondrial mass, subunits II and IV of complex IV, global and specific mitochondrial enzymatic and oxidative activities, and apoptosis from peripheral blood mononuclear cells. Global oxygen consumption was significantly compromised in HIV-infected untreated patients, compared to the control group (0.76 ± 0.01 versus 1.59 ± 0.15; P = 0.014). Apoptosis showed a trend to increase in untreated patients as well. The overall complex (C) CI-III-IV activity of the mitochondrial respiratory chain (MRC) was significantly decreased in HIV-infected treated patients with respect to the control group (1.52 ± 0.38 versus 6.38 ± 1.53; P = 0.02). No statistically significant differences were found between untreated and HAART-treated patients. These findings suggest the pathogenic role of both HIV and HAART in mitochondrial dysfunction in vertical infection. The abnormalities in mitochondrial genome may be downstream reflected through a global alteration of the MRC. Mitochondrial impairment associated with HIV and HAART was generalized, rather than localized, in this series of perinatally HIV-infected patients.

Mitochondrial toxicity and caspase activation in HIV pregnant women

“…The global adverse perinatal outcome were significantly increased in HIV pregnancies, but did not correlate with mitochondrial or apoptotic findings. Several studies have demonstrated mitochondrial toxicity in animal models, HIV-infected infants and adults on NRTI therapy and newborns exposed in utero to ARVs [22,24,37,38,47], but it is currently unknown whether HIV-pregnancy may be an additional risk for the onset of mitochondrial toxicity.…”

“…Mitochondrial respiratory chain complex II+III (CII+III) enzymatic activities were measured by spectrophotometry according to Rustin et al [37,40] by following the increase in absorbance at 550 nm of reduced cytochrome c generation (complex III product) after succinate addition (complex II substrate). Specific enzymatic activities were expressed as nanomols of product per minute and milligram of protein (nmols/ min.mg prot).…”

“…The few studies on long‐term HAART exposure have focused on foetal and perinatal ARV effects 32, 33, 34, 35, 36, 37, but rarely on maternal‐related problems which may, in turn, affect children.…”

“…Although ARV use during pregnancy is considered safe, data on ARV and pregnancy, especially in HAART, are insufficient, and safety and long-term health consequences are currently unknown. The few studies on long-term HAART exposure have focused on foetal and perinatal ARV effects [32][33][34][35][36][37], but rarely on maternal-related problems which may, in turn, affect children.…”

Mitochondrial DNA disturbances and deregulated expression of oxidative phosphorylation and mitochondrial fusion proteins in sporadic inclusion body myositis

“…This PBMC model is widely feasible for the evaluation of mitochondrial function [21][22][23]. Thus, we designed the present study to evaluate mitochondrial dysfunction in both muscle and PBMCs of sIBM patients to correlate dysfunction severity with genetic and molecular mitochondrial alterations, and determine their potential association with the deregulation of mitochondrial dynamics.…”