Developmental regulation of fetal mitochondrial respiratory function towards term: the role of glucocorticoid and thyroid hormones

Abstract

Mitochondria are unique intracellular organelles that have their own DNA and are inherited intact in the oocyte. They have multiple functions, the most important of which is producing energy in the form of ATP by oxidative phosphorylation (OXPHOS) using a range of metabolic substrates. As energy requirements increase with intrauterine growth and the onset of new postnatal functions at birth, mitochondria develop structurally and functionally in utero to meet these energy demands. In part, the developmental and prepartum maturational changes in mitochondrial OXPHOS capacity depend on the endocrine environment and the natural rise in the fetal concentrations of hormones, such as cortisol and tri-iodothyronine (T3), towards term. This review discusses the development of mitochondrial respiratory function during late gestation with an emphasis on tissue OXPHOS capacity. It considers the role of cortisol and thyroid hormones, in particular, in the intrauterine development and prepartum maturation of mitochondrial OXPHOS capacity in preparation for extrauterine life. Finally, it briefly examines the potential longer-term consequences of abnormal hormonal exposure before birth on mitochondrial OXPHOS function later in postnatal life. Endocrine regulation of mitochondrial OXPHOS in the fetus is shown to be multifactorial, dynamic and tissue specific with a central role in determining functional development. It optimises energetics for survival both in utero and at birth and has implications for adult metabolic fitness and the inheritance of mitochondrial phenotype.

Keywords: glucocorticoids; mitochondria; oxidative phosphorylation; thyroid hormones.

Figure 1

Schematic diagram showing the mitochondrial electon transfer system (ETS) and metabolic pathways contributing to the production of ATP and steroids. OMM = outer mitochondrial membrane. IMM = inner mitochondrial membrane. The blue ovals and circles represent the ETS comprising complexes I, II, II, IV and F1/Fo ATP synthase (also known as CV), electron transfer flavoprotein (ETF), Coenzyme Q (Q, also known as ubiquinone) and cytochrome c (c). The pink boxes represent the transmembrane transporter and carrier molecules as follows: ANT = adenine nucleotide transporter, CPT system = carnitine palmitoyl transferase, BCAA carriers = branched chain amino acids carriers, MPC = mitochondrial pyruvate carrier, and the hormone receptor transporters. The yellow stars indicate the sites of ROS production within the ETS, and the uncoupling proteins (UCP) are represented with an orange box. The white boxes show metabolic processes, including the tricarboxylic acid (TCA) cycle, beta-oxidation, glycolysis, plus the enzymes pyruvate dehydrogenase (PDH) and glutamate dehydrogenase (GDH), and the H+ electrochemical gradient across the IMM (ΔμH+). The green box shows the enzyme P450 side chain cleavage (P450scc), which produces pregnenolone (P5) from cholesterol in steroidogenic tissues.

Figure 2

The mean (±SEM) values of (A) protein abundance of the ETS complexes I to IV and ATP synthase (CV). (B) Gene expression of uncoupling protein 2 (UCP2) and adenine transporter 1 (ANT1) that affect the efficiency of oxidative phosphorylation (OXPHOS). (C) Rates of the total OXPHOS (black columns) and OXPHOS supported specifically by pyruvate (open columns) or palmitoyl-carnitine (grey columns) in the biceps femoris muscle of fetal sheep with respect to gestational age. Term ≥145 days. For each protein, gene and OXPHOS rate, values with different letters are significantly different from each other with respect to the gestational age (one way ANOVA, P < 0.05). Data from references (29, 30).

Figure 3

The mean (±SEM) values of (A) mitochondrial density measured as citrate synthase activity and gene expression of PGC1α, (B) oxidative phosphorylation (OXPHOS) capacity measured as rates of total, pyruvate and palmitoyl-carnitine supported OXPHOS, (C) protein abundance of the electron transfer (ETS) complexes (C) I to IV and ATP synthase (CV) and (D) gene expression of uncoupling protein 2 (UCP2) and adenine transporter 1 (ANT1) that affect OXPHOS efficiency in the biceps femoris of sheep fetuses at 143 days of gestation that were sham operated as controls (Con, open columns), adrenalectomised (AX, grey columns) or thyroidectomised (TX, black columns) earlier in gestation. Term ≥145 days. Values with different letters are significantly different from each other with respect to treatment (one way ANOVA, P < 0.05). *Significantly different from the control value P < 0.01 (t-test). Data from references (29,30).

Figure 4

The mean (±SEM) values of (A) mitochondrial density measured as citrate synthase activity, (B) oxidative phosphorylation (OXPHOS) capacity measured as rates of total, pyruvate and palmitoyl-carnitine supported OXPHOS, (C) protein abundance of the electron transfer (ETS) complexes I to IV and ATP synthase (CV) and (D) gene expression of uncoupling protein 2 (UCP2) and adenine transporter 1 (ANT1) that affect OXPHOS efficiency in the biceps femoris of sheep fetuses at 130 days of gestation after infusing saline as a control (Sal, open columns) or cortisol (Cort, Stripped columns) for the previous 5 days. Term ≥145 days *Significantly different from the saline infused control value P < 0.01, # Trend, P < 0.10, (t-test). Data from references (29, 30).

Figure 5

Schematic summary diagram showing the effects of cortisol and thyroid hormones on feto–placental mitochondria during intrauterine development and their subsequent consequences for the mitochondrial phenotype in both individuals and across generations. T₄ = thyroxine, T₃ = tri-iodothyronine, ETS = electron transfer system, ROS = reactive oxygen species, mtDNA = mitochondrial DNA, red circle = damaged mtDNA, Δ = change.