Cited by 203Cardiac Ischemia and ReperfusionMitochondrial Function and PathologyCancer, Hypoxia, and Metabolism

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

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Zhang, Jimmy, Wang, Yves T., Miller, James H., Day, Mary M., Munger, Joshua C., Brookes, Paul S.·2018·Cell Reports

Abstract

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.

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Crossref · 10.1016/j.celrep.2018.04.104

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  • FH loss in renal cancer cells leads to increased DNA damage and resistance to ionising radiation due to fumarate-dependent inhibition of mitotic entry after IR even with unrepaired damage.

    “It has also recently been shown that FH loss in renal cancer cells leads to increased DNA damage and resistance to ionising radiation (IR), due to a fumarate-dependent inhibition of mitotic entry after IR, even in the presence of unrepaired damage179.”

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Authors
Zhang, J., Wang, Y. T., Miller, J. H., Day, M. M., Munger, J. C., & Brookes, P. S.
Affiliations
University of Rochester Medicine (US)
Corresponding author
Brookes, Paul S.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-05
Volume
23
Issue
9
Pages
2617-2628
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2805060476
Cited by
203
References
51
Citations by year
2026: 29 · 2025: 20 · 2024: 21 · 2023: 31 · 2022: 30 · 2021: 27 · 2020: 27 · 2019: 16 · 2018: 2
FWCI
13.69
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • American Historical Association (F30-HL134203, 17PRE33410360)
  • National Institutes of Health (R01-HL071158)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
succinate accumulation, myocardial ischemia, TCA cycle, cardiomyocytes, anaplerosis, succinyl-CoA synthetase, substrate-level phosphorylation, ischemia-reperfusion injury, succinate oxidation, myocardial energetics
MeSH terms
Transaminases, Animals, Aspartic Acid, Autophagy, Citric Acid Cycle, Energy Metabolism, Glycolysis, Male, Mice, Inbred C57BL, Oxidation-Reduction, Reperfusion Injury, Myocardial Ischemia, Reactive Oxygen Species, Succinic Acid, Electron Transport Complex II, Glycogenolysis

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