Rhodoquinone carries electrons in the mammalian electron transport chain

Jonathan Valeros¹, Madison Jerome¹, Tenzin Tseyang¹, Paula Vo¹, Thang Do¹, Diana Fajardo Palomino², Nils Grotehans¹, Manisha Kunala², Alexandra E Jerrett², Nicolai R Hathiramani³, Michael Mireku¹, Rayna Y Magesh⁴, Batuhan Yenilmez¹, Paul C Rosen⁵, Jessica L Mann⁵, Jacob W Myers¹, Tenzin Kunchok⁶, Tanner L Manning⁷, Lily N Boercker⁷, Paige E Carr⁷, Muhammad Bin Munim⁵, Caroline A Lewis¹, David M Sabatini⁸, Mark Kelly⁹, Jun Xie¹⁰, Michael P Czech¹¹, Guangping Gao¹², Jennifer N Shepherd⁷, Amy K Walker¹, Hahn Kim¹³, Emma V Watson¹⁴, Jessica B Spinelli¹⁵

Affiliations

¹ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.
² 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.
³ 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.
⁴ Department of Systems Biology, UMass Chan Medical School, Worcester, MA 01605, USA.
⁵ Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁶ Whitehead Institute, Cambridge, MA 02142, USA.
⁷ Department of Chemistry and Biochemistry, Gonzaga University, Spokane, WA 99258, USA.
⁸ 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.
⁹ 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.
¹⁰ Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA 01605, USA.
¹¹ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA; Diabetes Center of Excellence, UMass Chan Medical School, Worcester, MA 01605, USA.
¹² 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.
¹³ Small Molecule Screening Center, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
¹⁴ Diabetes Center of Excellence, UMass Chan Medical School, Worcester, MA 01605, USA.
¹⁵ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA. Electronic address: jessica.spinelli@umassmed.edu.

PMID: 39909039
PMCID: PMC11845293 (available on 2026-02-20)
DOI: 10.1016/j.cell.2024.12.007

Rhodoquinone carries electrons in the mammalian electron transport chain

Jonathan Valeros et al. Cell. 2025.

. 2025 Feb 20;188(4):1084-1099.e27.

doi: 10.1016/j.cell.2024.12.007. Epub 2025 Feb 4.

Authors

Affiliations

¹ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.
² 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.
³ 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.
⁴ Department of Systems Biology, UMass Chan Medical School, Worcester, MA 01605, USA.
⁵ Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁶ Whitehead Institute, Cambridge, MA 02142, USA.
⁷ Department of Chemistry and Biochemistry, Gonzaga University, Spokane, WA 99258, USA.
⁸ 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.
⁹ 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.
¹⁰ Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA 01605, USA.
¹¹ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA; Diabetes Center of Excellence, UMass Chan Medical School, Worcester, MA 01605, USA.
¹² 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.
¹³ Small Molecule Screening Center, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
¹⁴ Diabetes Center of Excellence, UMass Chan Medical School, Worcester, MA 01605, USA.
¹⁵ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA. Electronic address: jessica.spinelli@umassmed.edu.

PMID: 39909039
PMCID: PMC11845293 (available on 2026-02-20)
DOI: 10.1016/j.cell.2024.12.007

Abstract

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.

Keywords: electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone.

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Conflict of interest statement

Declaration of interests J.B.S. and D.M.S. are co-inventors on a patent filed by the Whitehead Institute and UMass Chan Medical School on the uses of rhodoquinone for the treatment of disease. J.B.S. and H.K. are co-inventors on the patent application filed by the UMass Chan Medical School and Princeton University on the composition and usages of compounds for rhodoquinone-ETC-related diseases. H.K. is a co-founder, director, stockholder, and consultant for Crescenta Biosciences Inc. and Farber Partners LLC; a co-founder and shareholder of Chiromics LLC; and a shareholder and scientific advisor to Colorado Research Partners LLC and Integrated Biosciences Inc.

References

1. Spinelli JB, and Haigis MC (2018). The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol 20, 745–754. 10.1038/s41556-018-0124-1. - DOI - PMC - PubMed
1. Martinez-Reyes I, and Chandel NS (2020). Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 11, 102. 10.1038/s41467-019-13668-3. - DOI - PMC - PubMed
1. Osellame LD, Blacker TS, and Duchen MR (2012). Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab 26, 711–723. 10.1016/j.beem.2012.05.003. - DOI - PMC - PubMed
1. Spinelli JB, Rosen PC, Sprenger HG, Puszynska AM, Mann JL, Roessler JM, Cangelosi AL, Henne A, Condon KJ, Zhang T, et al. (2021). Fumarate is a terminal electron acceptor in the mammalian electron transport chain. Science 374, 1227–1237. 10.1126/science.abi7495. - DOI - PMC - PubMed
1. Monzel AS, Enriquez JA, and Picard M (2023). Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nat Metab 5, 546–562. 10.1038/s42255-023-00783-1. - DOI - PMC - PubMed

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Rhodoquinone carries electrons in the mammalian electron transport chain

Affiliations

Rhodoquinone carries electrons in the mammalian electron transport chain

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials