Gas regulation of complex II reversal via electron shunting to fumarate in the mammalian ETC

The electron transport chain (ETC) is a major currency converter that exchanges the chemical energy of fuel oxidation to proton motive force and, subsequently, ATP generation, using O2 as a terminal electron acceptor. Discussed herein, two new studies reveal that the mammalian ETC is forked. Hypoxia or H2S exposure promotes the use of fumarate as an alternate terminal electron acceptor. The fumarate/succinate and CoQH2/CoQ redox couples are nearly iso-potential, revealing that complex II is poised for facile reverse electron transfer, which is sensitive to CoQH2 and fumarate concentrations. The gas regulators, H2S and •NO, modulate O2 affinity and/or inhibit the electron transfer rate at complex IV. Their induction under hypoxia suggests a mechanism for how traffic at the ETC fork can be regulated.