The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart

The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart

In the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primar...

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Main Authors: Jennifer Q. Kwong, Xiyuan Lu, Robert N. Correll, Jennifer A. Schwanekamp, Ronald J. Vagnozzi, Michelle A. Sargent, Allen J. York, Jianyi Zhang, Donald M. Bers, Jeffery D. Molkentin
Format: Article
Language:English
Published: Elsevier 2015-07-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124715005859
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spelling doaj-24c55190390241b081190447c3450bdc2020-11-25T00:18:21ZengElsevierCell Reports2211-12472015-07-01121152210.1016/j.celrep.2015.06.002The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the HeartJennifer Q. Kwong0Xiyuan Lu1Robert N. Correll2Jennifer A. Schwanekamp3Ronald J. Vagnozzi4Michelle A. Sargent5Allen J. York6Jianyi Zhang7Donald M. Bers8Jeffery D. Molkentin9Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Pharmacology, University of California-Davis, Davis, CA 95616, USADepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Medicine, Leilihei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USADepartment of Pharmacology, University of California-Davis, Davis, CA 95616, USADepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USAIn the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca2+ uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu in the adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca2+ levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca2+ after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30 min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca2+ loading underlying a “fight-or-flight” response that acutely matches cardiac workload with ATP production.http://www.sciencedirect.com/science/article/pii/S2211124715005859
collection DOAJ
language English
format Article
sources DOAJ
author Jennifer Q. Kwong
Xiyuan Lu
Robert N. Correll
Jennifer A. Schwanekamp
Ronald J. Vagnozzi
Michelle A. Sargent
Allen J. York
Jianyi Zhang
Donald M. Bers
Jeffery D. Molkentin
spellingShingle Jennifer Q. Kwong
Xiyuan Lu
Robert N. Correll
Jennifer A. Schwanekamp
Ronald J. Vagnozzi
Michelle A. Sargent
Allen J. York
Jianyi Zhang
Donald M. Bers
Jeffery D. Molkentin
The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
Cell Reports
author_facet Jennifer Q. Kwong
Xiyuan Lu
Robert N. Correll
Jennifer A. Schwanekamp
Ronald J. Vagnozzi
Michelle A. Sargent
Allen J. York
Jianyi Zhang
Donald M. Bers
Jeffery D. Molkentin
author_sort Jennifer Q. Kwong
title The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
title_short The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
title_full The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
title_fullStr The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
title_full_unstemmed The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
title_sort mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2015-07-01
description In the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca2+ uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu in the adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca2+ levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca2+ after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30 min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca2+ loading underlying a “fight-or-flight” response that acutely matches cardiac workload with ATP production.
url http://www.sciencedirect.com/science/article/pii/S2211124715005859
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