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

Cell Reports
Jimmy ZhangPaul S Brookes

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.

Citations

Jul 19, 2019·EMBO Reports·Tao WangQing-Yan Jiang
Jul 6, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Yves T WangPaul S Brookes
Jan 17, 2020·Circulation Research·Tyler M Bauer, Elizabeth Murphy
Dec 17, 2019·Journal of Radiation Research·Michalina GramatykaMaria Sokół
Oct 23, 2019·Nature Reviews. Nephrology·Cissy YongChristian Frezza
May 10, 2020·Journal of Cellular and Molecular Medicine·Coert J ZuurbierThomas Krieg
Jul 16, 2020·Cardiovascular Research·Alexander S Milliken, Paul S Brookes
Aug 17, 2020·ELife·Chaitanya A KulkarniPaul S Brookes
Aug 9, 2020·Cardiovascular Research·Hiran A PragDunja Aksentijević
Aug 14, 2020·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Rahel K WyssSarah L Longnus
Apr 30, 2019·Nature Metabolism·Dylan G RyanEvanna L Mills
Apr 9, 2020·Metabolites·Emanuela LocciErnesto d'Aloja
Jun 26, 2020·Frontiers in Physiology·Iñigo San-MillánTravis Nemkov
Mar 29, 2020·Clinical Science·Xiao-Feng ChenXiaoqiang Tang
Jul 12, 2020·The Journal of Experimental Biology·Georgina K Cox, Todd E Gillis
May 13, 2020·Nature Metabolism·Jack L MartinMichael P Murphy
Aug 9, 2019·The International Journal of Biochemistry & Cell Biology·Christos Chinopoulos
Mar 9, 2019·JACC. Basic to Translational Science·Ven G LimDerek M Yellon
Jan 24, 2021·Free Radical Biology & Medicine·Maija DambrovaMarina Makrecka-Kuka
Sep 22, 2020·Trends in Molecular Medicine·Kourosh Saeb-ParsyMichael P Murphy
Jan 1, 2021·Free Radical Biology & Medicine·Chidozie N OkoyeCollins Kamunde
Oct 23, 2020·Nature Reviews. Cancer·Julie-Aurore LosmanWilliam G Kaelin
Feb 6, 2021·Journal of Clinical Medicine·Ram B KhattriTerence E Ryan
Feb 10, 2021·Redox Biology·Federica De LazzariMarco Bisaglia
Feb 9, 2020·Experimental Neurology·Christos Chinopoulos
Mar 7, 2021·International Journal of Molecular Sciences·Jan HaasBenjamin Meder
Apr 24, 2021·Free Radical Biology & Medicine·Tania Martins-MarquesHenrique Girao
Mar 6, 2021·Circulation·Jiyoung BaeAhmed I Mahmoud
Feb 19, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Daniel J HerrDonald R Menick
Nov 4, 2021·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Chidozie N OkoyeCollins Kamunde
Dec 3, 2021·Science·Jessica B SpinelliDavid M Sabatini
Dec 10, 2021·Biochemical Society Transactions·Shona A MookerjeeMartin D Brand

❮ Previous
Next ❯

Methods Mentioned

BETA
deamidation

Software Mentioned

MzRock
SIRM
XCalibur Qual Browser

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2022 Meta ULC. All rights reserved