Abstract 92: The Mitochondrial Calcium Uniporter is Necessary for Metabolic Matching of Contractile Demand During Acute Sympathetic Stress
Contractility is mediated by a variable flux in intracellular calcium (Ca2+), which is proposed to be integrated into mitochondria to regulate cardiac energetics. Moreover, mCa2+-overload is known to activate the mitochondrial permeability transition pore (MPTP) and induce cell death. Recent studies have reported that the Mcu gene encodes the channel-forming portion of the mitochondrial calcium uniporter (MCU) and is required for mCa2+ uptake. To examine the role of mCa2+ in the heart, we generated a conditional, cardiac-specific knockout model and deleted Mcu in adult mice (Mcu-cKO). Loss of Mcu protected against myocardial ischemia-reperfusion (IR) injury by preventing the activation of the MPTP. In addition while we found no baseline phenotype, Mcu-cKO mice lacked contractile responsiveness to beta-adrenergic receptor stimulation as assessed by invasive hemodynamics (Fig 1) and in parallel were unable to activate mitochondrial dehydrogenases and increase cardiac NADH levels. Further experimental analyses in isolated adult cardiomyocytes confirmed a lack of energetic responsiveness to acute sympathetic stress (isoproterenol failure to mediate an increase in NADH, Fig 2), supporting the hypothesis that the physiological function of the MCU in the heart is to modulate Ca2+-dependent metabolism during the ‘fight or flight’ response.
Author Disclosures: T.S. Luongo: None. J.P. Lambert: None. A. Yuan: None. X. Zhang: None. S. Shanmughapriya: None. E. Gao: None. S.R. Houser: None. M. Madesh: None. J.W. Elrod: None.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).
- © 2015 by American Heart Association, Inc.