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

Tyler P. Rasmussen, 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. Wagnerd, Jamie Soto, Michael L. McCormick, William Kutschke, Robert M. Weiss, Liping Yu, Ryan L. Boudreau, E. Dale Abel, Fenghuang Zhan, Douglas R. SpitzGarry R. Buettner, Long Sheng Song, Leonid V. Zingmanb, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Myocardial mitochondrial Ca2+ entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca2+ are lacking. We developed a mouse model with myocardial delimited transgenic expression of a dominant negative (DN) form of the mitochondrial Ca2+ uniporter (MCU). DN-MCU mice lack MCU-mediated mitochondrial Ca2+ 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 Ca2+ were not increased compared with WT, suggesting that DN-MCU expression increased OCR by enhanced energetic demands related to extramitochondrial Ca2+ homeostasis. Consistent with this, we found that DN-MCU ventricular cardiomyocytes exhibited elevated cytoplasmic [Ca2+] that was partially reversed by ATP dialysis, suggesting that metabolic defects arising from loss of MCU function impaired physiological intracellular Ca2+ homeostasis. Mitochondrial Ca2+ 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 Ca2+ homeostasis, reprogram transcription, increase OCR, reduce performance, and prevent anticipated therapeutic responses to ischemia-reperfusion injury.

Original languageEnglish (US)
Pages (from-to)9129-9134
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - Jul 21 2015


  • Ischemia-reperfusion injury
  • Mitochondrial calcium uniporter
  • Myocardium

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart'. Together they form a unique fingerprint.

Cite this