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

Jessica B. Spinelli*, Paul C. Rosen, Hans Georg Sprenger, Anna M. Puszynska, Jessica L. Mann, Julian M. Roessler, Andrew L. Cangelosi, Antonia Henne, Kendall J. Condon, Tong Zhang, Tenzin Kunchok, Caroline A. Lewis, Navdeep S. Chandel, David M. Sabatini

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1227-1237
Number of pages11
Issue number6572
StatePublished - Dec 3 2021

ASJC Scopus subject areas

  • General


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