Metabolon formation regulates branched-chain amino acid oxidation and homeostasis

McKenzie K. Patrick, Zhimin Gu, Gen Zhang, R. Max Wynn, Pranita Kaphle, Hui Cao, Hieu Vu, Feng Cai, Xiaofei Gao, Yuannyu Zhang, Mingyi Chen, Min Ni, David T. Chuang, Ralph J. DeBerardinis, Jian Xu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The branched-chain aminotransferase isozymes BCAT1 and BCAT2, segregated into distinct subcellular compartments and tissues, initiate the catabolism of branched-chain amino acids (BCAAs). However, whether and how BCAT isozymes cooperate with downstream enzymes to control BCAA homeostasis in an intact organism remains largely unknown. Here, we analyse system-wide metabolomic changes in BCAT1- and BCAT2-deficient mouse models. Loss of BCAT2 but not BCAT1 leads to accumulation of BCAAs and branched-chain α-keto acids (BCKAs), causing morbidity and mortality that can be ameliorated by dietary BCAA restriction. Through proximity labelling, isotope tracing and enzymatic assays, we provide evidence for the formation of a mitochondrial BCAA metabolon involving BCAT2 and branched-chain α-keto acid dehydrogenase. Disabling the metabolon contributes to BCAT2 deficiency-induced phenotypes, which can be reversed by BCAT1-mediated BCKA reamination. These findings establish a role for metabolon formation in BCAA metabolism in vivo and suggest a new strategy to modulate this pathway in diseases involving dysfunctional BCAA metabolism.

Original languageEnglish (US)
Pages (from-to)1775-1791
Number of pages17
JournalNature Metabolism
Issue number12
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology


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