Placental mitochondria in high-altitude pregnancy: metabolic adaptations and a toolkit for respiratory assessment

Ascent to high altitude is accompanied by physiological responses that, to an extent, mitigate the challenge of hypobaric hypoxia, maintaining arterial oxygen content and convective oxygen delivery. Nevertheless, arterial oxygen tension (pO₂) remains low and tissue hypoxia persists, posing a challenge for metabolic and redox homeostasis, and therefore function. The physiological challenge of life at high altitude is well exemplified by human pregnancy. Infant birthweight falls at high altitude, and there is a greater incidence of pregnancy complications, such as preeclampsia and fetal growth restriction; however, relative protection is seen in Tibetan and Andean populations. There is evidence to implicate a role for placental metabolic reprogramming and mitochondrial alterations in this context, while metabolic adaptations likely contribute to an integrated response that supports healthy pregnancies in highlander populations at altitude. Here, we outline the evidence to support a role for placental mitochondria in healthy and pathological pregnancies at high altitude. We propose that a better understanding of placental metabolic responses to tissue hypoxia would have important implications both for pregnancies at high altitude and in complicated pregnancies more generally, and we outline technical developments that allow the comprehensive assessment of placental mitochondrial respiration in an integrated, physiologically relevant context.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.