Dysfunction of Mitochondrial Ca²⁺ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases

Calcium ions (Ca²⁺) play critical roles in neuronal processes, such as signaling pathway activation, transcriptional regulation, and synaptic transmission initiation. Therefore, the regulation of Ca²⁺ homeostasis is one of the most important processes underlying the basic cellular viability and function of the neuron. Multiple components, including intracellular organelles and plasma membrane Ca²⁺-ATPase, are involved in neuronal Ca²⁺ control, and recent studies have focused on investigating the roles of mitochondria in synaptic function. Numerous mitochondrial Ca²⁺ regulatory proteins have been identified in the past decade, with studies demonstrating the tissue- or cell-type-specific function of each component. The mitochondrial calcium uniporter and its binding subunits are major inner mitochondrial membrane proteins contributing to mitochondrial Ca²⁺ uptake, whereas the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) and mitochondrial permeability transition pore (mPTP) are well-studied proteins involved in Ca²⁺ extrusion. The level of cytosolic Ca²⁺ and the resulting characteristics of synaptic vesicle release properties are controlled via mitochondrial Ca²⁺ uptake and release at presynaptic sites, while in dendrites, mitochondrial Ca²⁺ regulation affects synaptic plasticity. During brain aging and the progress of neurodegenerative disease, mitochondrial Ca²⁺ mishandling has been observed using various techniques, including live imaging of Ca²⁺ dynamics. Furthermore, Ca²⁺ dysregulation not only disrupts synaptic transmission but also causes neuronal cell death. Therefore, understanding the detailed pathophysiological mechanisms affecting the recently discovered mitochondrial Ca²⁺ regulatory machineries will help to identify novel therapeutic targets. Here, we discuss current research into mitochondrial Ca²⁺ regulatory machineries and how mitochondrial Ca²⁺ dysregulation contributes to brain aging and neurodegenerative disease.