Figure 4.

Dual role of complex I reverse electron transfer in pathology and physiology. (a) Complex I (CxI) reverse electron transfer (RET) in pathology. Factors that affect RET in ischemia reperfusion (IR) injury. During ischemia, succinate accumulation drives RET at complex II forcing electrons to complex I, where ROS is subsequently overproduced. Complex I has two states, active (A) and dormant (D). Ischemia drives an A-form that transition to D-form. During reperfusion D-form transition back to A-form generating reactive oxygen species (ROS) that causes IR injury. The mitochondrial protonmotive force (Δp) is a main driving force for RET. Therefore, decreasing the Δp removes a main driver of RET and ROS production at reperfusion. (b) Complex I reverse electron transfer contributes to diverse physiologic processes. The site-specific ROS production has a role in oxygen (O₂) sensing, lifespan extension, cell differentiation, and supercomplex formation.