The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders

Abstract

Mitochondrial calcium (Ca²⁺ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca²⁺ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca²⁺ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca²⁺ signaling at the molecular level. The biological function of Ca²⁺ channels and transporters as well as the role of mitochondrial Ca²⁺ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca²⁺ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca²⁺ homeostasis and also mitochondrial functions have expanded the number of targeted treatments. The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.

Keywords: Alzheimer's disease; ageing; calcium signaling; cellular homeostasis; mitochondria-associated ER membrane; therapeutic strategy.