Placental mitochondrial dysfunction with metabolic diseases: Therapeutic approaches

Abstract

Both obesity and gestational diabetes mellitus (GDM) lead to poor maternal and fetal outcomes, including pregnancy complications, fetal growth issues, stillbirth, and developmental programming of adult-onset disease in the offspring. Increased placental oxidative/nitrative stress and reduced placental (trophoblast) mitochondrial respiration occur in association with the altered maternal metabolic milieu of obesity and GDM. The effect is particularly evident when the fetus is male, suggesting a sexually dimorphic influence on the placenta. In addition, obesity and GDM are associated with inflexibility in trophoblast, limiting the ability to switch between usage of glucose, fatty acids, and glutamine as substrates for oxidative phosphorylation, again in a sexually dimorphic manner. Here we review mechanisms underlying placental mitochondrial dysfunction: its relationship to maternal and fetal outcomes and the influence of fetal sex. Prevention of placental oxidative stress and mitochondrial dysfunction may improve pregnancy outcomes. We outline pathways to ameliorate deficient mitochondrial respiration, particularly the benefits and pitfalls of mitochondria-targeted antioxidants.

Keywords: Antioxidants; Gestational diabetes; Mitochondria; Obesity; Oxidative stress; Placenta.

Figure 1.. The consequence of programming in utero.

The maternal state affects placental and fetal development (programming). On reaching adulthood, the programmed individual may start this cycle anew, creating a pattern for future disease.

Figure 2.. Overview of major aerobic metabolic pathways.

Glucose, fatty acids, and amino acids can all undergo oxidative metabolism in the mitochondria with one primary goal: ATP generation.

Figure 3.. Cellular sites of action of different agents for targeted reduction of oxidative stress.

Each letter represents an antioxidant-targeted component of the mitochondria or the cytoplasm.