BK channels in Cardiac physiology - Mitochondria have been shown to play a central role in cardiac contractility and the process is tightly regulated by electron transport chain (ETC) efficiency. Mitochondrial functions including ATP generation and ROS production by ETC are tightly coupled with ionic homeostasis and coordinated regulated signaling between nuclear-cytoplasmic and mitochondrial components. Tremendous progress has been made in deciphering the mechanistic role of mitochondria in protecting the heart from cardiac hypertrophy in animal models. Yet, it remains a substantial challenge to dissect the critical contribution of mitochondria to cardiac hypertrophy and to establish a rigorous relationship between energetics, signaling pathways, and specific aspects of cellular and organ hypertrophy. The potassium channel sensitive to voltage and calcium (BK) present in cardiomyocytes has been shown as a splice variant of plasma membrane BK and is exclusively present in mitochondrial membranes (referred to as mitoBK). Though activation of cardiac mitoBK is known to play a role in cardioprotection possibly by regulation of mitochondrial function, the precise mechanism of mitoBK in regulating cardiac function and protecting the heart from pathological hypertrophy (or cardioprotection from IR injury) is not yet established. We will now test the hypotheses that: cardiac mitoBK protects against pathological cardiac hypertrophy by regulating mitochondrial biogenesis and function via modulating the levels of UCPs, through signaling pathways governed by PGC-1α, and FOXO3a. Our published, as well as preliminary data, show that: 1) mitoBKCa is encoded by Kcnma1 gene, and a DEC splice variant governs its mitochondrial localization; 2) absence of mitoBK causes cardiac hypertrophy, fibrosis, and cardiac dysfunction; 3) absence of mitoBK augment cardiac hypertrophy after pressure overload insult whereas genetic activation protects the heart, 4) expression of mitoBK is vital for handing mitochondrial calcium and ROS levels after pressure overload, 5) absence of mitoBK results in changes in expression of UCPs, PGC-1α, and FOXO3a. Our preliminary data support our hypothesis that cardiac mitoBK, exclusively present in the mitochondria of adult cardiomyocytes, plays a cardioprotective role in cardiac hypertrophy. This will be tested by an array of multidisciplinary collaborative approaches using mouse genetics. In that regard, we will pursue the following specific aims: 1) To determine the role and mechanisms of mitoBK channel mediated changes in mitochondrial function in left ventricular hypertrophy; and 2) To elucidate mechanisms whereby retrograde signaling influences mitoBK activity, and expression of transcriptional coactivators and UCPs in left ventricular hypertrophy. This research program will be the first proposal that will determine the precise signaling mechanism of how cardiac mitoBK channels directly play a role in mitochondrial physiology, and cardiac function, and protect the heart from pathological cardiac hypertrophy.
