Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity

Succinate accumulates during ischemia, and its oxidation at reperfusion drives injury. The mechanism of ischemic succinate accumulation is controversial and is proposed to involve reversal of mitochondrial complex II. Herein, using stable-isotope-resolved metabolomics, we demonstrate that complex II reversal is possible in hypoxic mitochondria but is not the primary succinate source in hypoxic cardiomyocytes or ischemic hearts. Rather, in these intact systems succinate primarily originates from canonical Krebs cycle activity, partly supported by aminotransferase anaplerosis and glycolysis from glycogen. Augmentation of canonical Krebs cycle activity with dimethyl-α-ketoglutarate both increases ischemic succinate accumulation and drives substrate-level phosphorylation by succinyl-CoA synthetase, improving ischemic energetics. Although two-thirds of ischemic succinate accumulation is extracellular, the remaining one-third is metabolized during early reperfusion, wherein acute complex II inhibition is protective. These results highlight a bifunctional role for succinate: its complex-II-independent accumulation being beneficial in ischemia and its complex-II-dependent oxidation being detrimental at reperfusion. [Display omitted] •Canonical Krebs cycle, rather than complex II reversal, generates ischemic succinate•Ischemic succinate accumulation may improve ischemic energetics•At reperfusion, succinate is primarily washed out rather than oxidized Although succinate drives reperfusion injury, its ischemic accumulation mechanism is controversial. Herein, Zhang et al. show that ischemic succinate is generated by canonical Krebs cycle activity, rather than by mitochondrial complex II reversal, and improves ischemic energetics. At reperfusion, most succinate is washed out and may serve a signaling role.