Edward T. Chouchani, Victoria R. Pell, Edoardo Gaude et al.
The authors investigate the mechanism of ischaemia-reperfusion (IR), which occurs when the blood supply to a tissue is disrupted and then restored, such as during a heart attack or stroke. It is already well-established that tissue damage occurs once blood supply is restored, as this causes the electron transport chain to run in reverse: using ATP to pump protons into the mitochondrial matrix, generating reactive oxygen species (ROS) and inducing cell death. This study shows that accumulation of succinate is a universal feature of ischaemia, due to complex II reversal at low oxygen concentration. After reperfusion, the large amount of succinate drives conventional electron transport in complex III and IV, whilst driving complex I to run in reverse, to generate ROS. The authors show that inhibition of complex II ameliorates reperfusion injury. This cardiprotection is lost again when dimethyl succinate is added back, indicating that succinate elimination is the key protective feature of complex II inhibition.