Journal article
Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart
Proceedings of the National Academy of Sciences - PNAS, Vol.112(29), pp.9129-9134
07/21/2015
DOI: 10.1073/pnas.1504705112
PMCID: PMC4517214
PMID: 26153425
Abstract
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 O2 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.
Details
- Title: Subtitle
- Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart
- Creators
- Tyler P Rasmussen - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Yuejin Wu - Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287Mei-ling A Joiner - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Olha M Koval - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Nicholas R Wilson - Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287Elizabeth D Luczak - Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287Qinchuan Wang - Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287Biyi Chen - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Zhan Gao - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Zhiyong Zhu - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Brett A Wagner - Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242Jamie Soto - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Michael L McCormick - Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242William Kutschke - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Robert M Weiss - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Liping Yu - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Nuclear Magnetic Resonance Core Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52242Ryan L Boudreau - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242E Dale Abel - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242Fenghuang Zhan - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Douglas R Spitz - Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242Garry R Buettner - Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242Long-Sheng Song - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Leonid V Zingman - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Mark E Anderson - Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; mark.anderson@jhmi.edu
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.112(29), pp.9129-9134
- DOI
- 10.1073/pnas.1504705112
- PMID
- 26153425
- PMCID
- PMC4517214
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences; United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS R01 HL113001 / NHLBI NIH HHS R01 HL079031 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS U54 HL112311 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS R01 CA182804 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS I01 BX000718 / BLRD VA F30 HL114258 / NHLBI NIH HHS R01 DK092412 / NIDDK NIH HHS F30HL114258-02 / NHLBI NIH HHS R01 HL096652 / NHLBI NIH HHS S10 RR026293 / NCRR NIH HHS R01 HL090905 / NHLBI NIH HHS P30 DK079637 / NIDDK NIH HHS S10 RR026293-01 / NCRR NIH HHS
- Language
- English
- Date published
- 07/21/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Biology; Radiation Oncology; Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024505802771
Metrics
31 Record Views