The mitochondrial calcium uniporter complex (MCUcx) is essential for regulating calcium (Ca2+) homeostasis, which activates the TCA cycle, boosts oxidative phosphorylation (OXPHOS), and enhances ATP production. This complex is composed of the mitochondrial Ca2+ uniporter (MCU) pore-forming subunits and its dominant-negative variant, MCUb, the essential MCU regulator (EMRE), mitochondrial Ca2+ uptake regulatory subunits (MICU1, MICU2 and MICU3), and possibly other modulators such as MCU regulator 1 (MCUR1). Together, this complex acts in the inner mitochondrial membrane (IMM) to selectively mediate Ca2+ transport into the mitochondrial matrix (MM). Dysregulation of this process can lead to mitochondrial Ca2+ (mCa2+) overload, resulting in the opening of the mitochondrial permeability transition pore (mPTP) and apoptosis. In various diseases, such as cancer, myopathies, neurodegenerative, cardiovascular, and metabolic disorders, disruptions in MCUcx components affect mitochondrial function, leading to increased ROS, membrane depolarization, and activation of multiple signaling pathways. MCUcx is also involved in inflammatory responses, including activating the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome, which increases interleukin (IL)-1β and IL-18 production. Thus, MCUcx is a promising therapeutic target for various diseases, and further research into its role in cellular functions and disease mechanisms is essential for developing effective treatments.