From passage to inhibition: Uncovering the structural and physiological inhibitory mechanisms of MCUb in mitochondrial calcium regulation

Mitochondrial calcium (Ca(2+)) regulation is critically implicated in the regulation of bioenergetics and cell fate. Ca(2+), a universal signaling ion, passively diffuses into the mitochondrial intermembrane space (IMS) through voltage‐dependent anion channels (VDAC), where uptake into the matrix is tightly regulated across the inner mitochondrial membrane (IMM) by the mitochondrial Ca(2+) uniporter complex (mtCU). In recent years, immense progress has been made in identifying and characterizing distinct structural and physiological mechanisms of mtCU component function. One of the main regulatory components of the Ca(2+) selective mtCU channel is the mitochondrial Ca(2+) uniporter dominant‐negative beta subunit (MCUb). The structural mechanisms underlying the inhibitory effect(s) exerted by MCUb are poorly understood, despite high homology to the main mitochondrial Ca(2+) uniporter (MCU) channel‐forming subunits. In this review, we provide an overview of the structural differences between MCUb and MCU, believed to contribute to the inhibition of mitochondrial Ca(2+) uptake. We highlight the possible structural rationale for the absent interaction between MCUb and the mitochondrial Ca(2+) uptake 1 (MICU1) gatekeeping subunit and a potential widening of the pore upon integration of MCUb into the channel. We discuss physiological and pathophysiological information known about MCUb, underscoring implications in cardiac function and arrhythmia as a basis for future therapeutic discovery. Finally, we discuss potential post‐translational modifications on MCUb as another layer of important regulation.