Effects of in utero antiretroviral exposure on mitochondrial DNA levels, mitochondrial function and oxidative stress

Abstract

Objectives HIV and antiretroviral (ART) exposure in utero may have deleterious effects on the infant, but uncertainty still exists. The objective of this study was to evaluate aspects of mitochondrial DNA (mtDNA) content, mitochondrial function and oxidative stress simultaneously in placenta, umbilical cord blood and infant blood in HIV/ART-exposed infants compared with uninfected controls. Methods HIV-1-infected pregnant women and HIV-1-uninfected healthy pregnant controls were enrolled in the study prospectively. Placenta and umbilical cord blood were obtained at delivery and infant blood was obtained within 48 h of delivery. mtDNA content was determined for each specimen. Nuclear [subunit IV of cytochrome c-oxidase (COX IV)]- and mitochondrial (COX II)-encoded polypeptides of the oxidative phosphorylation enzyme cytochrome c-oxidase were quantified in cord and infant blood. Placental mitochondria malondialdehyde (MDA) concentrations were measured as a marker of oxidative stress. Results Twenty HIV-positive/HIV-exposed and 26 control mother–infant pairs were enrolled in the study. All HIV-infected women and their infants received ART. Placental MDA concentration and mtDNA content in placenta and cord blood were similar between groups. The cord blood COX II:IV ratio was lower in the HIV-positive group than in the controls, whereas the infant peripheral blood mtDNA content was higher in the HIV-exposed infants, but the infant peripheral blood COX II:IV ratio was similar. No infant had clinical evidence of mitochondrial disease or acquired HIV infection. In multivariable regression analyses, the significant findings in cord and infant blood were both most associated with HIV/ART exposure. Conclusions HIV-exposed infants showed reduced umbilical cord blood mitochondrial enzyme expression with increased infant peripheral blood mitochondrial DNA levels, the latter possibly reflecting a compensatory mechanism to overcome HIV/ART-associated mitochondrial toxicity.

Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

“…The physiopathological mechanism of anemia is not well understood (17), but mitochondrial dysfunction can be clearly attributed to ZDV (19). The adverse effects of ZDV are concentration dependent.…”

Tolérance pour l’enfant des antirétroviraux durant la grossesse

“…La quantification de l'ADN mitochondrial révèle des valeurs plus basses chez les enfants exposés à la zidovudine. Parallèlement, l'activité enzymatique des complexes de la chaîne respiratoire codés par l'ADN mitochondrial est abaissée [18]. L'impact de cette altéra-tion mitochondriale -au-delà de l'hyperlactatémie asymptomatique -reste à définir, notamment sur le système nerveux central.…”

Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon

“…[1] Since then, concern has evolved regarding the short- and long-term effects of in utero ARVs on the developing fetus. Several studies have shown abnormalities in mitochondrial DNA (mtDNA) content, [2–8] aberrant mitochondrial morphology, [1, 3] respiratory chain compromise, [8, 9] and also significant mitochondriopathy presenting as seizures, cognitive delays, motor and cardiac dysfunction, and even death. [1, 10] …”

“…Therefore, several studies have evaluated other aspects of mitochondria such as mitochondrial histology, [1, 3] DNA content, [2–5] and OXPHOS enzyme activity. [8, 9] Another aspect of mitochondrial health includes the biochemical reactions which produce cellular metabolites or energy and localize to the mitochondria such as fatty-acid oxidation, glycolysis, and parts of amino-acid catabolism. Intermediary metabolites involved in these metabolic pathways include, but are not limited to, acylcarnitines (ACs) and amino acids (AAs), the latter of which includes branched-chain amino acids (BCAAs).…”