Branched-chain amino acid fermentation as an alternative mammalian electron sink

Hypoxia disrupts mitochondrial respiration and increases the NADH/NAD+ ratio, causing reductive stress. To maintain redox homeostasis, mammalian cells divert electrons toward fermentation. While fermentation in mammals typically involves lactate production, we identify the fermentation of branched-chain amino acids (BCAAs) as an alternative electron sink activated by hypoxia. The resulting metabolites are excreted in urine as a distinct mechanism for alleviating reductive stress. BCAA fermentation is catalyzed by lactate dehydrogenase (LDH) enzymes and is highly responsive to the NADH/NAD+ ratio. Consequently, BCAA fermentation products are sensitive biomarkers for reductive stress in human contexts ranging from resistance exercise to severe hypoxemia. Furthermore, we find that mouse sperm have evolved highly efficient BCAA fermentation, providing a specific metabolic strategy to support the anaerobic electron flow that facilitates flagellar hypermotility across mammalian sperm. Our work highlights an under-appreciated fate of BCAAs in response to reductive stress.