Abstract 16645: Abcc9 Contributes to Mitochondrial Katp Function and Protection From Cardiomyopathy
In response to intracellular energy supply, ATP-sensitive potassium (KATP) channels alter membrane potential and mediate cell stress response. The Abcc9 gene encodes the major regulatory subunit in the heart, sulfonylurea receptor 2 (SUR2), as well as smaller mitochondria-enriched proteins that contribute to sulfonylurea-insensitive KATP channels. Pharmacological studies suggest mitochondrial KATP channels are critical regulators of cell stress, however the molecular composition of this channel has been unclear. We now studied the role of KATP channels by deleting exon 5 of Abcc9. This strategy ablated expression of both full length SUR2 protein as well as the smaller mitochondrial 55 KDa protein. Homozygous exon 5 (Ex5) mice died within 14 days of birth with progressive cardiac contractile dysfunction. Diazoxide was found to depolarize mitochondria from wildtype cardiomyocytes but not Ex5 mitochondria, consistent with disrupted mitochondrial KATP channels. Ex5 mitochondria had a reduced cross sectional area (WT: 1.27±0.11 vs. Ex5: 0.67±0.04µm2, p<0.05), and Ex5 cardiomyocytes also exhibited reduced oxygen consumption(WT: 1.86±0.41 vs. Ex5: 0.61±0.14nmO2/s, p<0.05). Deletion of exons 14 to 18 in Abcc9 disrupts full length SUR2 but leaves intact the 55 KDa protein. To determine the contribution of the mitochondrial 55 KDa protein, we compared the ability of Ex14/18 and Ex5 cardiomyocytes to withstand H2O2-induced stress. H2O2 application resulted in a more rapid collapse of mitochondria membrane potential in Ex5 mitochondria (5.2±0.3s) compared to wildtype (15.1±0.6s) and Ex14/18 (13.1±0.6s) mitochondria. We conclude the Abcc9-encoded 55 KDa protein contributes to mitochondrial KATP channels, and that mitochondrial KATP channels mediate the acute stress associated with cardiac function in the neonatal window.
- © 2011 by American Heart Association, Inc.