Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart

Myocardial mitochondrial Ca ²⁺ entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca ²⁺ are lacking. We developed a mouse model with myocardial delimited transgenic expression of a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (29), p.9129-9134
Main Authors: Rasmussen, Tyler P, Yuejin Wu, Mei-ling A. Joiner, Olha M. Koval, Nicholas R. Wilson, Elizabeth D. Luczak, Qinchuan Wang, Biyi Chen, Zhan Gao, Zhiyong Zhu, Brett A. Wagner, Jamie Soto, Michael L. McCormick, William Kutschke, Robert M. Weiss, Liping Yu, Ryan L. Boudreau, E. Dale Abel, Fenghuang Zhan, Douglas R. Spitz, Garry R. Buettner, Long-Sheng Song, Leonid V. Zingman, Mark E. Anderson
Format: Article
Language:English
Subjects:
Adaptation, Physiological
adenosine triphosphate
animal models
Animals
Biological Sciences
Blood Pressure
Calcium
Calcium - metabolism
Calcium Channels - metabolism
Cardiac Pacing, Artificial
Cellular Reprogramming
Cytoplasm
Cytosol - drug effects
Cytosol - metabolism
Diastole
Electrocardiography
energy
Genes, Dominant
genetically modified organisms
Glucose - metabolism
Heart - physiopathology
Heart Ventricles - pathology
Heart Ventricles - physiopathology
Homeostasis
Ischemia
ischemia-reperfusion injury
Mice
Mitochondria
Mitochondria, Heart - drug effects
Mitochondria, Heart - metabolism
mitochondrial calcium uniporter
Myocardial Reperfusion
myocardium
Myocardium - metabolism
Myocardium - pathology
oxidative phosphorylation
oxygen
Oxygen Consumption
Prostaglandin-Endoperoxide Synthases - metabolism
Rodents
Sarcoplasmic Reticulum - metabolism
stress response
Stress, Physiological
supply balance
Transcription, Genetic
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Summary:Myocardial mitochondrial Ca ²⁺ entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca ²⁺ are lacking. We developed a mouse model with myocardial delimited transgenic expression of a dominant negative (DN) form of the mitochondrial Ca ²⁺ uniporter (MCU). DN-MCU mice lack MCU-mediated mitochondrial Ca ²⁺ entry in myocardium, but, surprisingly, isolated perfused hearts exhibited higher O ₂ consumption rates (OCR) and impaired pacing induced mechanical performance compared with wild-type (WT) littermate controls. In contrast, OCR in DN-MCU–permeabilized myocardial fibers or isolated mitochondria in low Ca ²⁺ were not increased compared with WT, suggesting that DN-MCU expression increased OCR by enhanced energetic demands related to extramitochondrial Ca ²⁺ homeostasis. Consistent with this, we found that DN-MCU ventricular cardiomyocytes exhibited elevated cytoplasmic [Ca ²⁺] that was partially reversed by ATP dialysis, suggesting that metabolic defects arising from loss of MCU function impaired physiological intracellular Ca ²⁺ homeostasis. Mitochondrial Ca ²⁺ overload is thought to dissipate the inner mitochondrial membrane potential (ΔΨm) and enhance formation of reactive oxygen species (ROS) as a consequence of ischemia-reperfusion injury. Our data show that DN-MCU hearts had preserved ΔΨm and reduced ROS during ischemia reperfusion but were not protected from myocardial death compared with WT. Taken together, our findings show that chronic myocardial MCU inhibition leads to previously unanticipated compensatory changes that affect cytoplasmic Ca ²⁺ homeostasis, reprogram transcription, increase OCR, reduce performance, and prevent anticipated therapeutic responses to ischemia-reperfusion injury. Mitochondrial Ca ²⁺ is a fundamental signal that allows for adaptation to physiological stress but a liability during ischemia-reperfusion injury in heart. On one hand, mitochondrial Ca ²⁺ entry coordinates energy supply and demand in myocardium by increasing the activity of matrix dehydrogenases to augment ATP production by oxidative phosphorylation. On the other hand, inhibiting mitochondrial Ca ²⁺ overload is promulgated as a therapeutic approach to preserve myocardial tissue following ischemia-reperfusion injury. We developed a new mouse model of myocardial-targeted transgenic dominant-negative mitochon
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1504705112