Mitochondria regulate inositol triphosphate-mediated Ca release triggered by voltage-dependent Ca entry in resistance arteries.

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