Lower Oxygen Consumption and Complex I Activity in Mitochondria Isolated from Skeletal Muscle of Fetal Sheep with Intrauterine Growth Restriction.

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower hind-limb oxygen consumption rates (OCR), indicating depressed mitochondrial oxidative phosphorylation capacity in their skeletal muscle. We hypothesized that OCRs are lower in skeletal muscle mitochondria from IUGR fetuses due to reduced electron transport chain (ETC) activity and lower abundances of Tricarboxylic Acid (TCA) cycle enzymes. IUGR sheep fetuses (n=12) were created with mid-gestation maternal hyperthermia and compared to control fetuses (n=12). At 132±1 days of gestation, biceps femoris muscles were collected, and the mitochondria were isolated. Mitochondria from IUGR muscle have 47% lower State 3 (Complex-I dependent) OCRs than controls, while State 4 (proton leak) OCRs were not different between groups. Furthermore, Complex I, but not Complex II or IV, enzymatic activity was lower in IUGR fetuses compared to controls. Proteomic analysis (n=6/group) identified 160 differentially expressed proteins between groups with 107 upregulated and 53 downregulated mitochondria proteins in IUGR fetuses compared to controls. Although no differences were identified in ETC subunit protein abundances, abundances of key TCA cycle enzymes (IDH3B, SUCLA2, and OGDH) were lower in IUGR mitochondria. IUGR mitochondria had a greater abundance of a hypoxia inducible protein, NADH dehydrogenase 1 alpha subcomplex 4-like 2, which is known to incorporate into Complex I and lower Complex I-mediated NADH oxidation. Our findings show that mitochondria from IUGR skeletal muscle adapts to hypoxemia and hypoglycemia by lowering Complex I activity and TCA cycle enzymes concentrations, which together act to lower OCR and NADH production/oxidation in IUGR skeletal muscle.