The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition.

Abstract

Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu(-/-) mice display no overt baseline phenotype and are protected against mCa(2+) overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu(-/-) mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca(2+)-dependent metabolism during acute stress.

• Authors: Timothy S Luongo, Jonathan P Lambert, Ancai Yuan, Xueqian Zhang, Polina Gross, Jianliang Song, Santhanam Shanmughapriya, Erhe Gao, Mohit Jain, Steven R Houser, Walter J Koch, Joseph Y Cheung, Muniswamy Madesh, John W Elrod
• Journal: Cell reports (Cell Rep) Vol. 12 Issue 1 Pg. 23-34 (Jul 07 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26119731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channels
• mitochondrial calcium uniporter
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels (genetics, metabolism)
• Cells, Cultured
• Energy Metabolism
• Mice
• Mice, Inbred C57BL
• Myocardial Contraction
• Myocardial Reperfusion Injury (metabolism)
• Myocytes, Cardiac (metabolism, physiology)
• Stress, Physiological