Language

English

Publication Date

9-9-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.187758

PMID

40923315

PMCID

PMC12487681

PubMedCentral® Posted Date

9-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic disorders. Metabolic flux analyses confirmed robust BCAT inhibition, with reduction of labeling of proximal and distal BCAA-derived metabolites in MMA hepatocytes. In vivo experiments verified the BCAT inhibition, but total levels of distal BCAA catabolite disease markers and clinical symptoms were not normalized, indicating contributions of substrates other than BCAA to these distal metabolite pools. Our study demonstrates the importance of understanding the underlying pathology of metabolic disorders for identification of therapeutic targets and the use of multiple, complementary models to evaluate them.

Keywords

Amino Acid Metabolism, Inborn Errors, Humans, Animals, Mice, Transaminases, Mitochondria, Disease Models, Animal, Amino Acids, Branched-Chain, Hepatocytes, Male, Female, Genetics, Metabolism, Amino acid metabolism

Published Open-Access

yes

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