Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion
- PMID: 28093764
- PMCID: PMC5471420
- DOI: 10.1113/JP273408
Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion
Abstract
Key points: Pre-ischaemic administration of aminooxiacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against ischaemia-reperfusion injury. The underlying mechanism remains unknown. We examined whether transient inhibition of the MAS during ischaemia and early reperfusion by AOA treatment could prevent mitochondrial damage at later reperfusion. The AOA treatment preserved mitochondrial respiratory capacity with reduced mitochondrial oxidative stress during late reperfusion to the same extent as ischaemic preconditioning (IPC). However, AOA treatment, but not IPC, reduced the myocardial interstitial concentration of tricarboxylic acid cycle intermediates at the onset of reperfusion. The results obtained in the present study demonstrate that metabolic regulation by inhibition of the MAS at the onset of reperfusion may be beneficial for the preservation of mitochondrial function during late reperfusion in an IR-injured heart.
Abstract: Mitochondrial dysfunction plays a central role in ischaemia-reperfusion (IR) injury. Pre-ischaemic administration of aminooxyacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against IR injury, although the underlying mechanism remains unknown. We hypothesized that a transient inhibition of the MAS during ischaemia and early reperfusion could preserve mitochondrial function at later phase of reperfusion in the IR-injured heart to the same extent as ischaemic preconditioning (IPC), which is a well-validated cardioprotective strategy against IR injury. In the present study, we show that pre-ischaemic administration of AOA preserved mitochondrial complex I-linked state 3 respiration and fatty acid oxidation during late reperfusion in IR-injured isolated rat hearts. AOA treatment also attenuated the excessive emission of mitochondrial reactive oxygen species during state 3 with complex I-linked substrates during late reperfusion, which was consistent with reduced oxidative damage in the IR-injured heart. As a result, AOA treatment reduced infarct size after reperfusion. These protective effects of MAS inhibition on the mitochondria were similar to those of IPC. Intriguingly, the protection of mitochondrial function by AOA treatment appears to be different from that of IPC because AOA treatment, but not IPC, downregulated myocardial tricarboxilic acid (TCA)-cycle intermediates at the onset of reperfusion. MAS inhibition thus preserved mitochondrial respiratory capacity and decreased mitochondrial oxidative stress during late reperfusion in the IR-injured heart, at least in part, via metabolic regulation of TCA cycle intermediates in the mitochondria at the onset of reperfusion.
Keywords: heart; ischemia-reperfusion; malate-aspartate shuttle; mitochondria; oxidative stress.
© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g001.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g002.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g003.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g004.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g005.gif)
![Figure 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g006.gif)
![Figure 7](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g007.gif)
![Figure 8](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g008.gif)
![Figure 9](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5471420/bin/TJP-595-3765-g009.gif)
Similar articles
-
Inhibition of the malate-aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection.Cardiovasc Res. 2010 Nov 1;88(2):257-66. doi: 10.1093/cvr/cvq205. Epub 2010 Jun 18. Cardiovasc Res. 2010. PMID: 20562422
-
Effects of fatty acids on cardioprotection by pre-ischaemic inhibition of the malate-aspartate shuttle.Clin Exp Pharmacol Physiol. 2012 Oct;39(10):878-85. doi: 10.1111/j.1440-1681.2012.05749.x. Clin Exp Pharmacol Physiol. 2012. PMID: 22831462
-
Metabolic fingerprint of ischaemic cardioprotection: importance of the malate-aspartate shuttle.Cardiovasc Res. 2011 Aug 1;91(3):382-91. doi: 10.1093/cvr/cvr051. Epub 2011 Feb 23. Cardiovasc Res. 2011. PMID: 21349875 Review.
-
Amino acid transamination is crucial for ischaemic cardioprotection in normal and preconditioned isolated rat hearts--focus on L-glutamate.Exp Physiol. 2010 Jan;95(1):140-52. doi: 10.1113/expphysiol.2009.049452. Epub 2009 Aug 28. Exp Physiol. 2010. PMID: 19717487
-
Protection of the ischaemic heart: investigations into the phenomenon of ischaemic preconditioning.Cardiovasc J Afr. 2009 Jan-Feb;20(1):43-51. Cardiovasc J Afr. 2009. PMID: 19287816 Free PMC article. Review.
Cited by
-
Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.J Am Heart Assoc. 2024 Apr 16;13(8):e033628. doi: 10.1161/JAHA.123.033628. Epub 2024 Apr 2. J Am Heart Assoc. 2024. PMID: 38563382 Free PMC article. Clinical Trial.
-
Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.Sci Rep. 2024 Jan 8;14(1):757. doi: 10.1038/s41598-024-51387-y. Sci Rep. 2024. PMID: 38191915 Free PMC article.
-
Targeting Mitochondrial Metabolism to Save the Failing Heart.Life (Basel). 2023 Apr 16;13(4):1027. doi: 10.3390/life13041027. Life (Basel). 2023. PMID: 37109556 Free PMC article. Review.
-
Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats.Front Cardiovasc Med. 2023 Feb 6;10:1005408. doi: 10.3389/fcvm.2023.1005408. eCollection 2023. Front Cardiovasc Med. 2023. PMID: 36815024 Free PMC article.
-
Physiological levels of cardiolipin acutely affect mitochondrial respiration in vascular smooth muscle cells.Curr Res Physiol. 2022 Dec 21;6:100097. doi: 10.1016/j.crphys.2022.100097. eCollection 2023. Curr Res Physiol. 2022. PMID: 36594049 Free PMC article.
References
-
- Barron JT, Gu L & Parrillo JE (1998). Malate‐aspartate shuttle, cytoplasmic NADH redox potential, and energetics in vascular smooth muscle. J Mol Cell Cardiol 30, 1571–1579. - PubMed
-
- Chen Q, Moghaddas S, Hoppel CL & Lesnefsky EJ (2006). Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J Pharmacol Exp Ther 319, 1405–1412. - PubMed
-
- Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cocheme HM, Reinhold J, Lilley KS, Partridge L, Fearnley IM, Robinson AJ, Hartley RC, Smith RA, Krieg T, Brookes PS & Murphy MP (2013). Cardioprotection by S‐nitrosation of a cysteine switch on mitochondrial complex I. Nature Med 19, 753–759. - PMC - PubMed
-
- Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb‐Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T & Murphy MP (2014). Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435. - PMC - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials