TRPM2 channels protect against cardiac ischemia-reperfusion injury: Role of mitochondria

Barbara A. Miller, Nicholas E. Hoffman, Salim Merali, Xue Qian Zhang, Ju Fang Wang, Sudarsan Rajan, Santhanam Shanmughapriya, Erhe Gao, Carlos A. Barrero, Karthik Mallilankaraman, Jianliang Song, Tongda Gu, Iwona Hirschler-Laszkiewicz, Walter J. Koch, Arthur M. Feldman, Muniswamy Madesh, Joseph Y. Cheung

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52 Scopus citations

Abstract

Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial dysfunction and the tricarboxylic acid cycle. Complexes I, III, and IV were down-regulated, whereas complexes II and V were up-regulated in KO-I/R compared with WT-I/R hearts. Western blots confirmed reduced expression of the Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had a lower mitochondrial membrane potential, mitochondrial Ca2+ uptake, ATP levels, and O 2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca2+ uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca2+ uptake was likely due to both lower ψm and MCU activity. Similar to isolated myocytes, O2 consumption and ATP levels were also reduced in KO hearts. Under a simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. Reactive oxygen species levels were also significantly higher in KO-I/R compared with WT-I/R heart slices, consistent with mitochondrial dysfunction in KO-I/R hearts. We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels.

Original languageEnglish (US)
Pages (from-to)7615-7629
Number of pages15
JournalJournal of Biological Chemistry
Volume289
Issue number11
DOIs
StatePublished - Mar 14 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Miller, B. A., Hoffman, N. E., Merali, S., Zhang, X. Q., Wang, J. F., Rajan, S., Shanmughapriya, S., Gao, E., Barrero, C. A., Mallilankaraman, K., Song, J., Gu, T., Hirschler-Laszkiewicz, I., Koch, W. J., Feldman, A. M., Madesh, M., & Cheung, J. Y. (2014). TRPM2 channels protect against cardiac ischemia-reperfusion injury: Role of mitochondria. Journal of Biological Chemistry, 289(11), 7615-7629. https://doi.org/10.1074/jbc.M113.533851