LAUSR

The second messenger Ca 2+ and the key metabolic organelle mitochondria are at the core of cardiac excitation-coupling. In the cardiac muscle, Ca2+ acts as a signaling molecule that governs gene expression, cardiac contraction, and activates metabolism.1 Mitochondria provide the majority of the ATP required for cardiac contraction, and mitochondrial Ca2+ (mCa2+) serves as a signal to enhance energy production by activating ATP synthase, pyruvate dehydrogenase (PDH), isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase.2 Yet, under conditions of cytosolic Ca2+ overload, this pleiotropic second messenger turns into a powerful trigger for the opening of the permeability transition pore, leading to mitochondrial dysfunction and cell death.2 Thus, mechanisms regulating mCa2+ influx and efflux are central to cardiac pathophysiology. The mitochondrial Ca2+ uniporter (MCU) is a multiprotein complex located in the inner mitochondrial membrane. It is composed of pore-forming proteins (the channel subunit MCU, and the MCU dominant-negative β subunit; MCUB), the short transmembrane regulator EMRE (essential MCU regulator), and regulatory proteins (MICU1, MICU2, MICU3, MCUR1; mitochondrial calcium uptake proteins 1, 2, and 3; and mitochondrial calcium uniporter regulator 1) that regulate the threshold and the cooperativity of channel opening.3–8 MCU and MCUB form hetero-oligomers to generate the pore-forming subunit, whereas EMRE plays a fundamental role in the interaction between the pore core subunits and the regulatory subunits. MCU currents and mCa2+ uptake vary among tissues, highlighting how this complex can adapt to tissue demands. Interestingly, MCU and MCUB show divergent expression profiles among tissues. For instance, MCU:MCUB ratio is low in the heart and high in the skeletal muscle. Moreover, the low MICU1:MCU ratio in the heart lowers the threshold for Ca2+ uptake but reduces the cooperativity of uniporter activation, therefore allowing beat-to-beat mCa2+ oscillations.9 Such differences in the MCU complex composition impact on the ability of mitochondria to take up Ca2+. They also raise an interesting possibility that the composition of the complex or the contribution of each MCU complex component might change in pathological conditions, affecting mCa2+ levels. Deletion of the MCU subunit in the adult cardiomyocytes showed that MCU is crucial for the maintenance of cardiac function both at baseline and after stress/increased workload.10,11 On the contrary, the contribution of MCUB to cardiac pathophysiology is unclear. In this issue of Circulation, Lambert et al12 characterize the contribution of MCUB to MCU complex regulation and function at baseline and during cardiac stress. Using a combination of genetics, biochemistry, and functional Ca2+ assays in cell culture, Lambert et al show that MCUB deletion causes dynamic changes in MCU complex assembly, leading to an increase in the functional uniporter © 2019 American Heart Association, Inc.