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 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 Anderson

Research output: Contribution to journalArticle

Abstract

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
Volume112
Issue number29
DOIs
StatePublished - Jul 21 2015

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Physiological Stress
Homeostasis
Reperfusion Injury
Reactive Oxygen Species
Mitochondrial Membrane Potential
Mitochondrial Membranes
Cardiac Myocytes
Reperfusion
Dialysis
Myocardium
Mitochondria
Ischemia
Adenosine Triphosphate
Wounds and Injuries
Therapeutics

Keywords

  • Ischemia-reperfusion injury
  • Mitochondrial calcium uniporter
  • Myocardium

ASJC Scopus subject areas

  • General

Cite this

Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. / Rasmussen, Tyler P.; Wu, Yuejin; Joiner, Mei Ling A; Koval, Olha M.; Wilson, Nicholas R.; Luczak, Elizabeth; Wang, Qinchuan; Chen, Biyi; Gao, Zhan; Zhu, Zhiyong; Wagnerd, Brett A.; Soto, Jamie; McCormick, Michael L.; Kutschke, William; Weiss, Robert M.; Yu, Liping; Boudreau, Ryan L.; Abel, E. Dale; Zhan, Fenghuang; Spitz, Douglas R.; Buettner, Garry R.; Song, Long Sheng; Zingmanb, Leonid V.; Anderson, Mark.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 29, 21.07.2015, p. 9129-9134.

Research output: Contribution to journalArticle

Rasmussen, TP, Wu, Y, Joiner, MLA, Koval, OM, Wilson, NR, Luczak, E, Wang, Q, Chen, B, Gao, Z, Zhu, Z, Wagnerd, BA, Soto, J, McCormick, ML, Kutschke, W, Weiss, RM, Yu, L, Boudreau, RL, Abel, ED, Zhan, F, Spitz, DR, Buettner, GR, Song, LS, Zingmanb, LV & Anderson, M 2015, 'Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 29, pp. 9129-9134. https://doi.org/10.1073/pnas.1504705112
Rasmussen, Tyler P. ; Wu, Yuejin ; Joiner, Mei Ling A ; Koval, Olha M. ; Wilson, Nicholas R. ; Luczak, Elizabeth ; Wang, Qinchuan ; Chen, Biyi ; Gao, Zhan ; Zhu, Zhiyong ; Wagnerd, Brett A. ; Soto, Jamie ; McCormick, Michael L. ; Kutschke, William ; Weiss, Robert M. ; Yu, Liping ; Boudreau, Ryan L. ; Abel, E. Dale ; Zhan, Fenghuang ; Spitz, Douglas R. ; Buettner, Garry R. ; Song, Long Sheng ; Zingmanb, Leonid V. ; Anderson, Mark. / Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 29. pp. 9129-9134.
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AU - Rasmussen, Tyler P.

AU - Wu, Yuejin

AU - Joiner, Mei Ling A

AU - Koval, Olha M.

AU - Wilson, Nicholas R.

AU - Luczak, Elizabeth

AU - Wang, Qinchuan

AU - Chen, Biyi

AU - Gao, Zhan

AU - Zhu, Zhiyong

AU - Wagnerd, Brett A.

AU - Soto, Jamie

AU - McCormick, Michael L.

AU - Kutschke, William

AU - Weiss, Robert M.

AU - Yu, Liping

AU - Boudreau, Ryan L.

AU - Abel, E. Dale

AU - Zhan, Fenghuang

AU - Spitz, Douglas R.

AU - Buettner, Garry R.

AU - Song, Long Sheng

AU - Zingmanb, Leonid V.

AU - Anderson, Mark

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N2 - 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.

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