Ca²⁺ in the Mitochondrial Intermembrane Space: A New Compartment Fueling Arrhythmias

It is well established that regulation of calcium (Ca²⁺) within the mitochondrial matrix is critical for maintaining the balance between cell survival and death. Under physiological conditions, moderate elevations in matrix Ca²⁺ enhance mitochondrial bioenergetics by stimulating dehydrogenases of the tricarboxylic acid cycle, promoting oxidative phosphorylation and ATP synthesis. However, excessive or sustained Ca²⁺ accumulation within the matrix can precipitate mPTP (mitochondrial permeability transition pore) opening, resulting in membrane depolarization, disruption of the electron transport chain, and increased reactive oxygen species (ROS) production, while also promoting the release of proapoptotic factors and activation of cell death pathways. This matrix-focused perspective has long dominated the field, often overlooking the potential complexity of Ca²⁺ signaling within other mitochondrial compartments such as the intermembrane space (IMS) and specialized regions where mitochondria closely interact with other organelles, such as the endoplasmic reticulum, sarcoplasmic reticulum (SR), and lysosomes.