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

Science. 2021 Dec 3;374(6572):1227-1237. doi: 10.1126/science.abi7495. Epub 2021 Dec 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Line
  • Cell Line, Tumor
  • Dihydroorotate Dehydrogenase / metabolism
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / metabolism
  • Electron Transport*
  • Electrons*
  • Female
  • Fumarates / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Oxygen / metabolism
  • Succinate Dehydrogenase / metabolism
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / metabolism


  • Dihydroorotate Dehydrogenase
  • Fumarates
  • Ubiquinone
  • Succinate Dehydrogenase
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Electron Transport Complex III
  • ubiquinol
  • Oxygen