Fumarate is a terminal electron acceptor in the mammalian electron transport chain
A circuit of electron flow in the mammalian ETC that maintains mitochondrial functions under oxygen limitation is delineated, finding that complex I and dihydroorotate dehydrogenase can still deposit electrons into the ETC when oxygen reduction is impeded.
Abstract
Description Reversing the chain The mitochondrial electron transport chain is a major part of cellular metabolism and plays key roles in both cellular respiration and the synthesis of critical metabolites. Typically, electrons flow through the electron transport chain in a specific direction, ending up with oxygen as the terminal electron acceptor. Spinelli et al. characterized an alternative path of electron flow through the transport chain, ending with fumarate as the electron acceptor (see the Perspective by Baksh and Finley). This pathway operates under conditions of limited oxygen availability, and the authors have confirmed its activity in vivo in a mouse model, observing that the propensity to use this pathway varied between organs. —YN Fumarate is a terminal electron acceptor in the mammalian electron transport chain, and its reduction sustains mitochondrial functions in hypoxia. 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.