Large conductance Ca2+- activated potassium (BK) channels are abundant in cardiomyocyte mitochondria, yet their physiological role in the intact heart has remained undefined. Here we show that genetic ablation of BK channels in mice produces global biventricular dysfunction, chamber dilation, and impaired aortic hemodynamics, revealing a previously unrecognized requirement for BK channels in maintaining cardiovascular performance. Transcriptomic profiling uncovered coordinated downregulation of all three mitochondrial uncoupling proteins (UCP1-3) and suppression of the PGC1alpha-FoxO3a transcriptional axis. Consistent with a causal link, pharmacologic activation of Beta 3 adrenergic receptors, an established inducer of UCP expression, restored UCP levels and fully rescued cardiac function in BK-deficient mice. These findings identify BK channels as upstream regulators of mitochondrial gene programs essential for cardiac homeostasis and uncover a mechanism by which ion channel signaling governs whole-organ physiology. Targeting BK-dependent mitochondrial pathways may offer new therapeutic strategies for heart failure.
Gururaja Rao, S., Patel, N., Patel, N. J., Shah, K., Hussain, A., Raut, S., Gowswami, S., Singh, S., Ponnalagu, D., Karekar, P., Addya, S., Accornero, F., Kohut, A., Singh, H.
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