Mitochondria regulate inositol triphosphate-mediated Ca²⁺ release triggered by voltage-dependent Ca²⁺ entry in...

An increase in cytoplasmic Ca²⁺ concentration activates multiple cellular activities, including cell division, metabolism, growth, contraction and death. In smooth muscle Ca²⁺ entry via voltage-dependent Ca²⁺ channels leads to a relatively uniform increase in cytoplasmic Ca²⁺ levels that facilitates co-ordinated contraction throughout the cell. However certain functions triggered by voltage-dependent Ca²⁺ channels require periodic, pulsatile Ca²⁺ changes. The mechanism by which Ca²⁺ entry through voltage-dependent channels supports both co-ordinated contraction and distinct cellular responses driven by pulsatile Ca²⁺ changes is unclear. Here in intact resistance arteries we show that Ca²⁺ entry via voltage-dependent Ca²⁺ channels evokes Ca²⁺ release via inositol triphosphate receptors (IP₃Rs), generating repetitive Ca²⁺ oscillations and waves. We also show that mitochondria play a vital role in regulating Ca²⁺ signals evoked by voltage-dependent Ca²⁺ entry by selectively modulating Ca²⁺ release via IP₃Rs. Depolarizing the mitochondrial membrane inhibits Ca²⁺ release from internal stores, reducing the overall signal-generated Ca²⁺ influx without altering the signal resulting from voltage-dependent Ca²⁺ entry. Notably neither Ca²⁺ entry via voltage-dependent Ca²⁺ channels nor Ca²⁺ release via IP₃Rs alters mitochondrial location or mitochondrial membrane potential in intact smooth muscle cells. Collectively these results demonstrate that activation of voltage-dependent Ca²⁺ channels drives Ca²⁺ entry, which subsequently triggers Ca²⁺ release from the internal store in smooth muscle cells. Mitochondria selectively regulate this process by modulating IP₃R-mediated amplification of Ca²⁺ signals, ensuring that different cellular responses are precisely controlled. KEY POINTS: In smooth muscle Ca²⁺ entry via voltage-dependent channels produces a uniform Ca²⁺ increase, enabling co-ordinated contraction in each cell. Certain functions, however, require large, pulsatile Ca²⁺ changes rather than a uniform increase. Using advanced imaging in intact arteries, we discovered that voltage-dependent Ca²⁺ entry triggers internal store Ca²⁺ release via IP₃ receptors, generating repetitive Ca²⁺ oscillations and waves. Mitochondria selectively modulate these signals by regulating only IP₃ receptor-mediated release; neither mitochondrial location nor membrane potential is altered by either type of Ca²⁺ signal. These findings demonstrate how voltage-dependent Ca²⁺ entry supports both co-ordinated contraction and pulsatile Ca²⁺-driven biological responses.