Cited by 221Mitochondrial Function and PathologyCancer, Hypoxia, and MetabolismAutophagy in Disease and Therapy

Fumarate is a terminal electron acceptor in the mammalian electron transport chain

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Spinelli, Jessica B., Rosen, Paul C., Sprenger, Hans-Georg, Puszynska, Anna M., Mann, Jessica L., Roessler, Julian M., Cangelosi, Andrew L., Henne, Antonia +6 more·2021·Science

Abstract

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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  • ETC inhibition can force the SDH complex to operate in reverse, reducing fumarate to produce succinate.

    “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).”
  • Reverse SDH activity allows the ETC to continue accepting electrons from other oxidation reactions, such as dihydroorotate dehydrogenase, which is critical for nucleotide biosynthesis.

    “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).”

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Research works printed but not linked: 3

  1. [6]Mick E, eLife 9, e49178 (2020).32463360
  2. [7]Condon KJ, Proc. Natl. Acad. Sci. U.S.A 118, e2022120118 (2021).33483422
  3. [37]Aloysius GM, Tielens AGM, Van Hellemond JJ, Biochim. Biophys. Acta Bioenerg 1365, 71– 78 (1998). 9693724

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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.
Venue
Science
Published
2021-12-03
Volume
374
Issue
6572
Pages
1227-1237
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
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
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
  • Health Sciences › Medicine › Epidemiology › 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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