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

Year: 2026
Type: preprint
Abstract: ABSTRACT 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.
DOI: 10.64898/2026.08.24.746737
Authors: Ayush D. Midha, Brandon T. L. Chew, Yolanda Martí-Mateos, Skyler Y. Blume, Will R. Flanigan, Brandon R. Desousa, Augustinus G. Haribowo, Aunoy Poddar, Saahil Chadha, Bruno B. Queliconi, Alec M. Barrios, Michela Traglia, Reuben Thomas, Junji Suzuki, Mito Kuroda, Steven J. Altschuler, Lani F. Wu, Yuriy Kirichok, Mercedes F. Paredes, Tracy G. Anthony, Polina V. Lishko, Isha H. Jain
Institutions: Gladstone Institutes, University of California, San Francisco, University of California, Berkeley, Arc Research Institute, Washington University in St. Louis, Rutgers, The State University of New Jersey
Subfield: Cancer Research
Open Access status: green
Funders: Arc Institute, National Science Foundation, Larry L. Hillblom Foundation, National Institutes of Health, Defense Advanced Research Projects Agency, Advanced Research Projects Agency, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: Graduate Research Fellowship Program (GRFP), G2237985346, G2431723542, G2515541506, G3778743365, G6308955451, G809596425, G8895715465, Systems genomics approach to targeting glucose toxicity during pathological cardiomyocyte hypoxia, Mechanisms of Oxygen Toxicity
OpenAlex ID: W7204209607
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