Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.

Department of Chemistry and Biochemistry Gonzaga University Spokane WA 99258 USA

Department of Systems Biology UMass Chan Medical School Worcester MA 01605 USA

Diabetes Center of Excellence UMass Chan Medical School Worcester MA 01605 USA

Horae Gene Therapy Center UMass Chan Medical School Worcester MA 01605 USA

Horae Gene Therapy Center UMass Chan Medical School Worcester MA 01605 USA; Li Weibo Institute for Rare Disease Research UMass Chan Medical School Worcester MA 01655 USA; Department of Microbiology and Physiological Systems UMass Chan Medical School Worcester MA 01605 USA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo n 2 166 10 Prague Czech Republic; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Boston Branch 840 Memorial Drive Cambridge MA 02139 USA

Massachusetts Institute of Technology Cambridge MA 02142 USA

Program in Molecular Medicine UMass Chan Medical School Worcester MA 01605 USA

Program in Molecular Medicine UMass Chan Medical School Worcester MA 01605 USA; Diabetes Center of Excellence UMass Chan Medical School Worcester MA 01605 USA

Program in Molecular Medicine UMass Chan Medical School Worcester MA 01605 USA; Division of Cardiovascular Medicine Department of Medicine UMass Chan Medical School Worcester MA 01605 USA

Program in Molecular Medicine UMass Chan Medical School Worcester MA 01605 USA; Morningside Graduate School of Biomedical Sciences UMass Chan Medical School Worcester MA 01605 USA

Program in Molecular Medicine UMass Chan Medical School Worcester MA 01605 USA; Morningside Graduate School of Biomedical Sciences UMass Chan Medical School Worcester MA 01605 USA; Diabetes Center of Excellence UMass Chan Medical School Worcester MA 01605 USA

Small Molecule Screening Center Princeton University Princeton NJ 08544 USA; Department of Chemistry Princeton University Princeton NJ 08544 USA

Whitehead Institute Cambridge MA 02142 USA

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