Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM2

Title: TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria.

Authors: Barbara A Miller, Nicholas E Hoffman, Salim Merali, Xue-Qian Zhang, Jufang 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

Journal, date & volume: J. Biol. Chem., 2014 Mar 14 , 289, 7615-29

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24492610

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 Ca(2+) uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca(2+) uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca(2+) 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.