Redox Control of Metabolism: How Fgr Kinase Shapes Mitochondrial Function and Cellular Adaptation

Mitochondria coordinate cellular energy production, metabolism, and signalling through the organization of the electron transport chain (ETC) and formation of respiratory supercomplexes. These structures facilitate efficient electron transfer and enable coenzyme Q (CoQ) channelling, allowing differential regulation of NADH- and succinate-driven respiration while modulating reactive oxygen species (ROS) production. Beyond their damaging potential, ROS act as key signalling molecules that regulate mitochondrial function through redox-sensitive modifications. Mitochondrial protein kinases add an additional layer of control, with Src-family kinases playing a central role. In particular, the mitochondrial tyrosine-kinase Fgr is activated by H2O2 and promotes phosphorylation of succinate dehydrogenase, boosting complex II activity, delivering more electrons to CoQ and inducing reverse electron transfer (RET) through CI, in a ROS-induced ROS generation amplification cycle. This induces a metabolic rewiring aimed at supporting stress adaptation, immune cell activation, and macrophage polarization. Overall, the interplay between supercomplex organization, ROS signalling, and kinase activity is critical for metabolic flexibility and represents a promising target for therapeutic intervention.