TRPM2 Channels Protect Against Cardiac Ischemia-Reperfusion Injury: Role of Mitochondria [Bioenergetics]

February 3rd, 2014 by Miller, B. A., Hoffman, N. E., Merali, S., Zhang, X.-Q., Wang, J., 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.

Cardiac TRPM2 channels were activated by intracellular ADPR 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 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 while complexes II and V were up-regulated in KO-I/R compared to WT-I/R hearts. Western blots confirmed reduced expression of Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had lower mitochondrial membrane potential,mitochondrial Ca2+ uptake, ATP levels and O2 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 simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. ROS levels were also significantly higher in KO-I/R compared to 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 ROS levels.