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

J Mol Cell Cardiol. 2023 Aug:181:33-45. doi: 10.1016/j.yjmcc.2023.05.007. Epub 2023 May 23.

Abstract

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.

Keywords: ATP; Calcium; Ischemia/reperfusion; Mitochondria; Mitochondrial calcium uniporter; Permeability transition pore.

Publication types

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

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Calcium / metabolism
  • Calcium Channels* / genetics
  • Calcium Channels* / metabolism
  • Mice
  • Mitochondria, Heart / metabolism
  • Mitochondrial Membranes* / metabolism

Substances

  • Adenosine Triphosphate
  • Calcium
  • Calcium Channels
  • mitochondrial calcium uniporter
  • Mcu protein, mouse
  • Emre protein, mouse