Figure 2.

The molecular mechanisms of succinate-driven formation of ROS. During ischemia, the high NADH/NAD⁺ ratio forces the MAS and purine nucleotide cycle (PNC) to produce excess fumarate (green arrows). Because of the high ubiquinol (QH₂) levels, succinate dehydrogenase (SDH, complex II) works in reverse and converts fumarate to succinate (green arrows). The accumulated succinate is rapidly oxidized during reperfusion, which leads to a surge in ROS production at complex I through reverse electron transfer (blue arrow). Excessive ROS production leads to MPT, collapse of the mitochondrial transmembrane potential (ΔΨ) and ultimately cell death. Additional details on the depicted signaling cascades are provided in the text (see Ischemia and Mitochondrial Metabolites). AS, adenylosuccinate; C, cytochrome c; IMP, inosine monophosphate; MPTP, mitochondrial permeability transition pore.