Fig. 6.

Cellular model for ITPKB function in PD. In healthy neurons (Top), the ER is the predominant storage organelle for intracellular calcium (Ca²⁺), which is transiently released in response to various upstream signaling events to mediate diverse cellular functions. ER Ca²⁺ can be released through either the IP₃R or the Ryanodine receptor (RyR), while the ER-cytosol Ca²⁺ gradient is preserved by SERCA. In response to increases in intracellular IP₃ levels, Ca²⁺ is released from the ER via IP₃Rs, leading to Ca²⁺ accumulation in mitochondria mediated by transport into the inner mitochondrial matrix via the mitochondrial calcium uniporter (MCU). Transient increases in mitochondrial calcium levels ([Ca²⁺]_mito) drive the production of ATP from ADP by oxidative phosphorylation. ITPKB enzymatic activity negatively regulates IP₃-mediated ER calcium release by converting IP₃ to IP₄, thereby protecting cells from overproduction of ATP and accumulation of ROS. The MCU subunits MICU1, MICU2, and MICU3 serve as Ca²⁺ sensors to control homeostatic levels of Ca²⁺ import into mitochondria. In PD (Bottom), loss of ITPKB activity, changes in MCU regulatory subunit composition, and/or chronic increases in intracellular IP₃ levels or sensitivity of IP₃Rs to IP₃ may contribute to increased [Ca²⁺]_mito, leading to ROS generation, mTOR activity, and the accumulation of misfolded proteins, including α-syn aggregates. Pharmacological agents that positively modulate ITPKB activity or inhibit ER-to-mitochondria calcium exchange may represent a new therapeutic approach for the treatment of synucleinopathies such as PD.