Corrigendum
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10.1172/jci.insight.187849
Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart
Joseph R. Visker, Ahmad A. Cluntun, Jesse N. Velasco-Silva, David R. Eberhardt, Luis Cedeño-Rosario, Thirupura S. Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J. Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S. Ducker, Stavros G. Drakos, and Jared Rutter
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Published November 8, 2024 - More info
JCI Insight. 2024;9(21):e187849. https://doi.org/10.1172/jci.insight.187849.
© 2024 Visker et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart; however, the rapid reintroduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the total myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and redirecting pyruvate toward oxidation can blunt hypertrophy. We hypothesized that this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. After I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ), and Ca2+, increased pyruvate entry to the TCA cycle, increased oxygen consumption, and improved myocardial salvage and functional outcomes following I/R. Our data suggest normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
Authors
Joseph R. Visker, Ahmad A. Cluntun, Jesse N. Velasco-Silva, David R. Eberhardt, Luis Cedeño-Rosario, Thirupura S. Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J. Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S. Ducker, Stavros G. Drakos, Jared Rutter
Original citation JCI Insight. 2024;9(17):e180906. https://doi.org/10.1172/jci.insight.180906
Citation for this corrigendum: JCI Insight. 2024;9(21):e187849. https://doi.org/10.1172/jci.insight.187849
After publication, the authors became aware of labeling issues in the paper. d-glucose was inadvertently referred to as l-glucose in the Methods. In addition, the key for Figures 3, G–J, was incorrectly assigned green to the hypoxia group and red to the hypoxia+regeneration group. The correct version of these panels is shown below. These errors have been corrected in the PDF and HTML versions of the manuscript.
The authors regret the error.
