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

作者：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. Wagner, Jamie E. Soto, Michael L. McCormick, William J. Kutschke, Robert M. Weiss, Liping P. Yu, Ryan L. Boudreau, E. Dale Abel, Fenghuang Zhan, Douglas R. Spitz, Garry R. Buettner, Long‐Sheng Song, Leonid V. Zingman, Mark E. Anderson · 发表于：Proceedings of the National Academy of Sciences · 年份：2015 · DOI：10.1073/pnas.1504705112 · 被引用次数：166 · 研究领域：Mitochondrial Function and Pathology、Cardiac Ischemia and Reperfusion、ATP Synthase and ATPases Research

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 f...