Compartmentalized metabolism supports midgestation mammalian development

Abstract

Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5–11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose’s contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle4,5. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5–GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero.

Comprehensive Analysis of Cuproptosis-Related Genes in Immune Infiltration and Prognosis in Melanoma

“…Lipoic acid is a pivotal cofactor for the 2-ketoacid dehydrogenases (pyruvate dehydrogenase complex, 2-oxoadipate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase) and the glycine cleavage system in mitochondria which are related to TCA cycle and mitochondrial energy metabolism and amino acid catabolism ( Hiltunen et al, 2010 ; Mayr et al, 2014 ; Stowe et al, 2018 ; Solmonson et al, 2022 ). Lipoyltransferase 1, encoded by LIPT1, transferred lipoate to the E2 subunits of the 2-ketoacid dehydrogenases ( Hiltunen et al, 2010 ; Stowe et al, 2018 ).…”

“…Thus, deficiency in the LIPT1 homolog could lead to decreased lipoylation of the E2 subunits ( Schonauer et al, 2009 ; Stowe et al, 2018 ). LIPT1 deficiency was also demonstrated to suppress TCA cycle metabolism ( Solmonson et al, 2022 ). LIPT1 has further been revealed to support lipogenesis and balance oxidative and reductive glutamine metabolism in the functional assessment ( Ni et al, 2019 ).…”

“…LIPT1 has further been revealed to support lipogenesis and balance oxidative and reductive glutamine metabolism in the functional assessment ( Ni et al, 2019 ). LIPT1 deficiency was reported in embryonic demise, early death or Leigh-like encephalopathy, such as early infantile epileptic encephalopathy, Leigh disease, secondary pyruvate dehydrogenase complex deficiency, fatal lactic acidosis ( Soreze et al, 2013 ; Habarou et al, 2017 ; Stowe et al, 2018 ; Solmonson et al, 2022 ). However, the role of LIPT1 in the tumorigenesis and progression of tumors is far to be known.…”

A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma

“…FDX1 may affect the prognosis of lung adenocarcinoma by mediating metabolism 21 . Lipoyltransferase 1 (LIPT1) is an enzyme that activates TCA cycle-associated 2-ketoacid dehydrogenases, and its deficiency inhibits the metabolism of the TCA cycle 22 . Dihydrolipamine dehydrogenase (DLD) was reported to modulate cysteine deprivation-induced ferroptosis 23 .…”

Single-cell transcriptomic profiling unveils dysregulation of cardiac progenitor cells and cardiomyocytes in a mouse model of maternal hyperglycemia

“…A recent study by Solmonson et al; have applied in vivo isotope tracing and metabolomics approach to reveal compartment-specific differences in glucose-6-phosphate and other metabolites. Their data reveals the contribution of maternally derived nutrients to embryonic glucose metabolism and identified metabolic transition at E10.5-E11.5 85 . This method will inform our understanding of the developmental consequences of intrauterine metabolic defects on metabolic transition in the intact fetoplacental unit.…”