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Fumarate is a terminal electron acceptor in the mammalian electron transport chain
Open accessAbstract
For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal electron acceptor (TEA), which is known to be oxygen in mammals. Paradoxically, we find that complex I and dihydroorotate dehydrogenase (DHODH) can still deposit electrons into the ETC when oxygen reduction is impeded. Cells lacking oxygen reduction accumulate ubiquinol, driving the succinate dehydrogenase (SDH) complex in reverse to enable electron deposition onto fumarate. Upon inhibition of oxygen reduction, fumarate reduction sustains DHODH and complex I activities. Mouse tissues display varying capacities to use fumarate as a TEA, most of which net reverse the SDH complex under hypoxia. Thus, we delineate a circuit of electron flow in the mammalian ETC that maintains mitochondrial functions under oxygen limitation.
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“For example, ETC inhibition, which prevents cells from using molecular oxygen as a terminal electron acceptor, can force the SDH complex to operate in reverse, reducing fumarate to produce succinate (129).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [129]
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“By siphoning electrons onto fumarate, reverse SDH activity allows the ETC to continue to accept electrons from other oxidation reactions, such as that catalyzed by dihydroorotate dehydrogenase, which is critical for nucleotide biosynthesis (129).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [129]
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Metadata
- Authors
- Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., Kunchok, T., Lewis, C. A., Chandel, N. S., & Sabatini, D. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Northwestern University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Spinelli, Jessica B.
- ORCID
- Venue
- Science
- Published
- 2021-12-03
- Volume
- 374
- Issue
- 6572
- Pages
- 1227-1237
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8803114
- OpenAlex
- W3217375757
- Cited by
- 221
- References
- 64
- Citations by year
- 2026: 36 · 2025: 55 · 2024: 49 · 2023: 43 · 2022: 37 · 2021: 1
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG049665)
- National Cancer Institute (R01CA219859, F31CA254162, K00CA234839, R35CA197532)
- National Institute of Diabetes and Digestive and Kidney Diseases (F31DK113665)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- fumarate, terminal electron acceptors, mitochondrial electron transport chain, dihydroorotate dehydrogenase, complex I, succinate dehydrogenase, ubiquinol, oxygen reduction reaction, hypoxia, reverse electron flow
- MeSH terms
- Dihydroorotate Dehydrogenase, Animals, Cell Line, Electron Transport Complex IV, Electron Transport, Electrons, Female, Fumarates, Humans, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Oxygen, Succinate Dehydrogenase, Electron Transport Complex III, Ubiquinone, Cell Hypoxia, Electron Transport Complex I, Cell Line, Tumor, Mice
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