Rhodoquinone carries electrons in the mammalian electron transport chain
Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O<sub>2</sub>). In hypoxia, ubiquinol (UQH<sub>2</sub>) 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 O<sub>2</sub> 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/O<sub>2</sub> 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.
Authors
- Emma V. Watson (ORCID: https://orcid.org/0000-0003-1321-6604)
- Amy K. Walker (ORCID: https://orcid.org/0000-0003-1899-8916)
- Jacob W. Myers (ORCID: https://orcid.org/0000-0002-0288-2161)
- Guangping Gao (ORCID: https://orcid.org/0000-0003-0097-9012)
- Jennifer N. Shepherd (ORCID: https://orcid.org/0000-0002-6926-6777)
- Tenzin Tseyang (ORCID: https://orcid.org/0009-0007-9410-3789)
- David M. Sabatini (ORCID: https://orcid.org/0000-0002-1446-7256)
- Madison Jerome (ORCID: https://orcid.org/0000-0002-0460-8481)
- Batuhan Yenilmez (ORCID: https://orcid.org/0000-0001-8798-3676)
- Caroline A. Lewis (ORCID: https://orcid.org/0000-0003-1787-5084)
- Tenzin Kunchok (ORCID: https://orcid.org/0000-0001-6603-4607)
- Nils Grotehans (ORCID: https://orcid.org/0009-0009-9418-267X)
- Jun Xie (ORCID: https://orcid.org/0000-0003-1402-4428)
- Philippa Carr (ORCID: https://orcid.org/0009-0003-2377-1756)
- Thomas C. Manning
- Nicolai Hathiramani
- Paula Vo (ORCID: https://orcid.org/0000-0002-1988-2168)
- Paul C. Rosen (ORCID: https://orcid.org/0000-0001-7414-454X)
- Alexandra E. Jerrett
- Jessica B. Spinelli (ORCID: https://orcid.org/0000-0003-3657-4578)
- Jessica L. Mann
- Michael Czech (ORCID: https://orcid.org/0000-0003-4075-7350)
- Mark Kelly (ORCID: https://orcid.org/0000-0001-9018-594X)
- Diana Fajardo Palomino (ORCID: https://orcid.org/0009-0003-7041-1841)
- Jonathan Valeros
- Muhammad Bin Munim
- Hahn Kim (ORCID: https://orcid.org/0000-0003-4180-6038)
- Rayna Y. Magesh (ORCID: https://orcid.org/0009-0007-8837-7521)
- T Do
- Michael Mireku
- Lily N. Boercker
- Manisha Kunala
Institutions
- Gonzaga University (US)
- UMass Memorial Health Care (US)
- University of Massachusetts Chan Medical School (US)
- Princeton University (US)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Whitehead Institute for Biomedical Research (US)
- UMass Memorial Medical Center (US)
- Massachusetts Institute of Technology (US)
- Morningside College (US)
Publication Details
- Journal
- Cell
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.cell.2024.12.007
- Citations
- 18
- Primary Topic
- Coenzyme Q10 studies and effects
- Type
- article
- Field-Weighted Citation Impact
- 14.51
Funders
- Richard and Susan Smith Family Foundation
- American Foundation for Aging Research
- Searle Scholars Program
- Worcester State Foundation
- National Institute on Aging
- National Institute of Diabetes and Digestive and Kidney Diseases
- Division of Diabetes, Endocrinology, and Metabolic Diseases