Placental mitochondria adapt developmentally and in response to hypoxia to support fetal growth

Abstract

Mitochondria respond to a range of stimuli and function in energy production and redox homeostasis. However, little is known about the developmental and environmental control of mitochondria in the placenta, an organ vital for fetal growth and pregnancy maintenance in eutherian mammals. Using respirometry and molecular analyses, the present study examined mitochondrial function in the distinct transport and endocrine zones of the mouse placenta during normal pregnancy and maternal inhalation hypoxia. The data show that mitochondria of the two zones adopt different strategies in modulating their respiration, substrate use, biogenesis, density, and efficiency to best support the growth and energy demands of fetoplacental tissues during late gestation in both normal and hypoxic conditions. The findings have important implications for environmentally induced adaptations in mitochondrial function in other tissues and for compromised human pregnancy in which hypoxia and alterations in placental mitochondrial function are associated with poor outcomes like fetal growth restriction.

Keywords: fetus; hypoxia; metabolism; mitochondria; placenta.

Fig. 1.

Mitochondrial respiration and associated protein abundance in the last third of pregnancy. (A and B) Oxygen consumption in LEAK and OXPHOS states using (A) Py and (B) Pal, (C) RCRs for Py and Pal, and (D) OXPHOS respiration in the presence of malate, glutamate, and succinate (GMS_P) in the placental Jz and Lz, as well as (E and F) protein abundance in the (E) Jz and (F) Lz at D14, D16, and D19 of pregnancy. Analyzed by two-way ANOVA (age and zone) with Bonferroni post hoc tests. Different letters represent a significant difference between gestational ages, within a zone (P < 0.05); * denotes a significant difference of Lz to Jz, for a given age (P < 0.05). Outcome of ANOVA is shown if pair-wise comparisons were not significant; n = 6 to 10 per age for A–D, and n = 5 to 6 for E and F per treatment. ATPase, ATP synthase; CI−IV, ETS complexes I to IV.

Fig. 2.

Mitochondrial respiration and associated protein abundance at D16 in response to hypoxia. (A and B) Oxygen consumption in LEAK and OXPHOS states using (A) Py and (B) Pal, (C) RCRs for Py and Pal, and (D) OXPHOS respiration in the presence of malate, glutamate and succinate (GMS_P) in the placental Jz and Lz, as well as (E and F) protein abundance in the (E) Jz and (F) Lz following exposure to 13% O₂ from D11 to D16 or pair feeding normoxic animals to the food intake of mice in 13% O₂ (PF). Analyzed by two-way ANOVA (treatment and zone) with Bonferroni post hoc tests. Different letters represent a significant difference between treatments, within a zone (P < 0.05); * denotes a significant difference of Lz to Jz (P < 0.05). Outcome of ANOVA is shown if pair-wise comparisons were not significant; n = 6 to 10 for A–D and n = 5 for E and F per treatment; txt, treatment.

Fig. 3.

Mitochondrial respiration and associated protein abundance at D19 in response to hypoxia. (A and B) Oxygen consumption in LEAK and OXPHOS states using (A) Py and (B) Pal, (C) RCRs for Py and Pal, and (D) OXPHOS respiration in the presence of malate, glutamate, and succinate (GMS_P) in the placental Jz and Lz, as well as (E and F) protein abundance in the (E) Jz and (F) Lz following exposure to 13% O₂ or 10% O₂ from D14 to D19 or pair feeding normoxic animals to the food intake of mice in 10% O₂ (PF). Analyzed by two-way ANOVA (treatment and zone) with Bonferroni post hoc tests; * denotes a significant difference of Lz to Jz (P < 0.05); different letters represent a significant difference between treatments, within a zone (P < 0.05). Outcome of ANOVA is shown if pair-wise comparisons were not significant; and # indicates a significant difference of 13% O₂ to N by t test (P < 0.05); n = 9 to 16 for A–D and n = 6 to 9 for E and F per treatment.