A Loss of Function of the Mitochondrial Branched-Chain Aminotransferase (BCATm) Leads to Increased Glycolytic and Oxidative Metabolism in Activated CD4+ T Cells. (29th May 2020)

• Record Type: Journal Article
• Authors: Ananieva, Elitsa; Toress, Ashley; Powell, Jonathan; Hutson, Susan; Boyer, Michael
• Is Part Of: Current developments in nutrition. Volume 4(2020)Supplement 2
• Page Start: 1517
• Page End: 1517
• Publication Date: 2020-05-29
• Subjects: Nutrition -- Periodicals; Nutritional Physiological Phenomena; Nutrition; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 612.3
• DOI: 10.1093/cdn/nzaa068_002
• Languages: English
• ISSNs: 2475-2991

Abstract

Abstract: Objectives: T cells use the amino acid leucine to respond to their increased biosynthetic demands during activation. However, once inside T cells, leucine is subjected to degradation, which is initiated by the mitochondrial branched-chain aminotransferase (BCATm) that catalyzes the reversible transamination of leucine. We hypothesized that if BCATm is absent from T cells, this would provide more intracellular leucine to stimulate T cell metabolism. Methods: To explore the dependence of T cells on BCATm function, we isolated CD4 + T cells from spleens of wild type (WT) and BCATm global knockout (KO) mice, and after cell activation with anti-CD3 and anti-CD28 for 24 h, we measured leucine transamination, glycolysis, mitochondrial respiration and ATP synthesis, the activity of the mammalian target of rapamycin (mTOR) pathway, and the release of IFN-γ. Results: The global deletion of BCATm resulted in a 1.8-fold reduction in leucine transamination and a 1.2-fold increase in the intracellular leucine concentrations in activated CD4 + T cells from BCATmKO mice. These T cells demonstrated 4.0– and 5.0-fold increases in glycolysis and glycolytic capacity, along with 1.8– and 2-0-fold increases in the maximal respiration and spare respiratory capacity when compared to WT T cells after 24 h of activation. In addition, mTOR signaling was more active in BCATmKO T cells and their IFN-γ release was increased by 2.1-fold relative to WT T cells. Conclusions: The results suggested that leucine catabolism at the BCATm step negatively affects T cell metabolism by limiting glycolytic intermediates for biosynthetic needs and mitochondrial respiration for energy. Thus, leucine catabolism is regarded as a metabolic checkpoint of T cells that may prove useful for therapeutic purposes. Funding Sources: Des Moines University, (IOER-112-3705 to EAS), the National Institute of Health (DK 34, 738 to SMH).