Absence (of the uniporter) makes the heart grow fonder: The cardiac response to injury adapts after prolonged EMRE inhibition

More than a decade after identifying the molecular components of the mitochondrial calcium uniporter, the main channel responsible for rapid mitochondrial Ca2+ uptake, questions remain regarding its modes of regulation during physiological and pathological stress. The uniporter complex comprises the pore-forming MCU subunit, targeting protein EMRE, gate-keeping proteins MICU 1, 2, and 3, and inhibitory subunit MCUB [ [1] Balderas E. Sommakia S. Eberhardt D. Lee S. Chaudhuri D. The Structural Era of the Mitochondrial Calcium Uniporter, Calcium Signals. IOP Publishing, 2023 Google Scholar ]. Maximal inhibition of rapid mitochondrial Ca2+ uptake can be obtained by genetic deletion of MCU, which prevents expression of the pore, or EMRE, which prevents accurate membrane targeting and assembly of MCU subunits into a channel. Intriguingly, prior studies have shown disparate results for cardiac uniporter deletion in the setting of stress, depending on the mechanism by which genetic deletion was achieved. In inducible cardiac-specific MCU knockouts, cardiac mitochondria are protected against ischemia-reperfusion (I/R) injury, and have a blunted response to β-adrenergic stimuli [ [2] Kwong J.Q. Lu X. Correll R.N. Schwanekamp J.A. Vagnozzi R.J. Sargent M.A. et al. The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Rep. 2015; 12: 15-22 Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar , [3] Luongo T.S. Lambert J.P. Yuan A. Zhang X. Gross P. Song J. et al. The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell Rep. 2015; 12: 23-34 Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar ]. Both of these were examined shortly after inducing the gene deletion. In contrast, germline ablation of MCU or EMRE resulted in no protection of the heart against I/R injury, and a preserved β-adrenergic response, phenotypes in these cases examined long after gene deletion [ [4] Liu J.C. Syder N.C. Ghorashi N.S. Willingham T.B. Parks R.J. Sun J. et al. EMRE is essential for mitochondrial calcium uniporter activity in a mouse model. JCI Insight. 2020; 5 Crossref Scopus (25) Google Scholar , [5] Pan X. Liu J. Nguyen T. Liu C. Sun J. Teng Y. et al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat. Cell Biol. 2013; 15: 1464-1472 Crossref PubMed Scopus (480) Google Scholar ]. Thus, a key knowledge gap regarding uniporter regulation has been whether these different phenotypes reflect endogenous adaptation occurring in the period between acute (for the inducible models) and chronic (for the germline models) deletion, or rather reflect epiphenomena of the particular models used. Answering this question is critical for understanding the consequences of therapies that attempt to modulate uniporter function.