Figure 1. Ca²⁺ flux into the mitochondria through global cytoplasmic Ca²⁺ and Ca²⁺ microdomains.

Mitochondria interact with organelles such as the endoplasmic reticulum (ER) through contact sites generating Ca²⁺ microdomains. These Ca²⁺ microdomains (left half), contain a multi-protein complex linking IP3R (an ER Ca²⁺ channel in purple) to VDAC (3D structure representation) in the mitochondrial outer member (MOM). The microdomains enable rapid transfer of Ca²⁺ (Ca²⁺ sparks) from the ER to mitochondria through VDAC and the MCU in the inner membrane (MIM). Global or capacitive uptake of Ca²⁺ from the cytosol (right half) is slower due to the lower local concentration of Ca²⁺compared to microdomains. Ca²⁺enters the cytosol from extracellular space or ER stores.