Distinct effects of cardiac mitochondrial calcium uniporter inactivation via EMRE deletion in the short and long term

Hector Chapoy Villanueva, Jae Hwi Sung, Jackie A. Stevens, Michael J. Zhang, Peyton M. Nelson, Lalitha S. Denduluri, Feng Feng, Timothy D. O'Connell, De Wayne Townsend, Julia C. Liu

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Transport of Ca2+ into mitochondria is thought to stimulate the production of ATP, a critical process in the heart's fight or flight response, but excess Ca2+ can trigger cell death. The mitochondrial Ca2+ uniporter complex is the primary route of Ca2+ transport into mitochondria, in which the channel-forming protein MCU and the regulatory protein EMRE are essential for activity. In previous studies, chronic Mcu or Emre deletion differed from acute cardiac Mcu deletion in response to adrenergic stimulation and ischemia/reperfusion (I/R) injury, despite equivalent inactivation of rapid mitochondrial Ca2+ uptake. To explore this discrepancy between chronic and acute loss of uniporter activity, we compared short-term and long-term Emre deletion using a novel conditional cardiac-specific, tamoxifen-inducible mouse model. After short-term Emre deletion (3 weeks post-tamoxifen) in adult mice, cardiac mitochondria were unable to take up Ca2+, had lower basal mitochondrial Ca2+ levels, and displayed attenuated Ca2+-induced ATP production and mPTP opening. Moreover, short-term EMRE loss blunted cardiac response to adrenergic stimulation and improved maintenance of cardiac function in an ex vivo I/R model. We then tested whether the long-term absence of EMRE (3 months post-tamoxifen) in adulthood would lead to distinct outcomes. After long-term Emre deletion, mitochondrial Ca2+ handling and function, as well as cardiac response to adrenergic stimulation, were similarly impaired as in short-term deletion. Interestingly, however, protection from I/R injury was lost in the long-term. These data suggest that several months without uniporter function are insufficient to restore bioenergetic response but are sufficient to restore susceptibility to I/R.

Original languageEnglish (US)
Pages (from-to)33-45
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
StatePublished - Aug 2023

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health [ 1K22HL137901 and 1R01HL164491 to J.C.L].

Publisher Copyright:
© 2023


  • ATP
  • Calcium
  • Ischemia/reperfusion
  • Mitochondria
  • Mitochondrial calcium uniporter
  • Permeability transition pore

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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