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

Cell Rep. 2018 May 29;23(9):2617-2628. doi: 10.1016/j.celrep.2018.04.104.


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.

Keywords: complex II; heart; ischemia; mitochondria; reperfusion; succinate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aspartic Acid / metabolism
  • Autophagy
  • Citric Acid Cycle*
  • Electron Transport Complex II / metabolism
  • Energy Metabolism
  • Glycogenolysis
  • Glycolysis
  • Male
  • Mice, Inbred C57BL
  • Myocardial Ischemia / metabolism*
  • Oxidation-Reduction
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Succinic Acid / metabolism*
  • Transaminases / metabolism


  • Reactive Oxygen Species
  • Aspartic Acid
  • Succinic Acid
  • Electron Transport Complex II
  • Transaminases