Here, the authors combine in vivo work with biochemical and cryo-EM analyses to characterize the effects of a P25L mutation in the ND6 subunit of mitochondrial complex I. They observe that this mutation does not affect oxidative phosphorylation but renders complex I unable to generate ROS by RET: ND6-P25L mice are protected against cardiac ischaemia–reperfusion injury, thus providing evidence for the proposed role of ROS production in myocardial infarction. This evidence concerns the gene MT-ND6 and myocardial infarction.