Mitochondrial Oxidative Metabolism Regulates Maternal-Fetal Metabolic Communication

mitochondrial metabolism;late-gestation;pregnancy;mitochondrial pyruvate carrier;MPC1;pyruvate;alanine;fatty acid;carnitine palmitoyltransferase 2 (Cpt2);malonyl-CoA;ACSF3;malonylation;Biochemistry

Bowman, Caitlyn ElizabethHart, Gerald W. ;

Johns Hopkins University

关键词: mitochondrial metabolism;    late-gestation;    pregnancy;    mitochondrial pyruvate carrier;    MPC1;    pyruvate;    alanine;    fatty acid;    carnitine palmitoyltransferase 2 (Cpt2);    malonyl-CoA;    ACSF3;    malonylation;    Biochemistry;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/59981/BOWMAN-DISSERTATION-2018.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Macronutrient metabolism includes the suite of chemical transformations that sustain cells and allow for organismal growth and development. Mammalian pregnancy is perhaps the most nutritionally sensitive stage in life as all nutrients for fetal growth are provided by the mother. Glucose and oxygen are two of the most important molecules transferred to the fetus, and their metabolic fates converge at the metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex that consists of two essential components, MPC1 and MPC2. Here we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. While Mpc1 deletion was lethal during mid-gestation, a hypomorphic knock-in (KI) allele of Mpc1 resulted in perinatal lethality. Late-gestation Mpc1 KI fetuses were smaller than littermates with tissue-specific compensatory changes in lipid and amino acid metabolism. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be partially mitigated by alternative anaplerotic substrates in utero.To further probe the capacity for metabolic plasticity in this model, late-gestation dams were fasted for 24 hours. Maternal fasting increased serum lipid metabolites, promoted fetal liver triglyceride accumulation, and stunted fetal growth. To determine the contribution of maternally-derived lipids to the fetal fasting response, we used two genetic models of impaired fatty acid oxidation: (1) liver-specific loss of mitochondrial β-oxidation of long-chain fatty acids via carnitine palmitoyltransferase 2 (Cpt2) and (2) genetic loss of a transcriptional regulator of lipid oxidative metabolism, PPARα. Upon fasting, these mice exhibit differing degrees of hepatic lipid accumulation and impaired ketogenesis. The fetal response to maternal fasting was determined by liver transcriptional program and steady-state metabolite measurements. The maternal fasting response is a better indicator of fetal outcome than is fetal genotype, suggesting that maternally-derived factors dominate this communication. Furthermore, maternal effects persist into the early postnatal period, highlighting the importance of maternal lipid metabolism during gestation and lactation. The use of genetic models and biochemical approaches to obtain a greater mechanistic understanding of maternal-fetal metabolic communication may inform interventions for conditions such as gestational diabetes.