Mitochondria regulate inositol triphosphate-mediated Ca(2+) release triggered by voltage-dependent Ca(2+) entry in resistance arteries.

An increase in cytoplasmic Ca(2+) concentration activates multiple cellular activities, including cell division, metabolism, growth, contraction and death. In smooth muscle Ca(2+) entry via voltage-dependent Ca(2+) channels leads to a relatively uniform increase in cytoplasmic Ca(2+) levels that facilitates co-ordinated contraction throughout the cell. However certain functions triggered by voltage-dependent Ca(2+) channels require periodic, pulsatile Ca(2+) changes. The mechanism by which Ca(2+) entry through voltage-dependent channels supports both co-ordinated contraction and distinct cellular responses driven by pulsatile Ca(2+) changes is unclear. Here in intact resistance arteries we show that Ca(2+) entry via voltage-dependent Ca(2+) channels evokes Ca(2+) release via inositol triphosphate receptors (IP(3)Rs), generating repetitive Ca(2+) oscillations and waves. We also show that mitochondria play a vital role in regulating Ca(2+) signals evoked by voltage-dependent Ca(2+) entry by selectively modulating Ca(2+) release via IP(3)Rs. Depolarizing the mitochondrial membrane inhibits Ca(2+) release from internal stores, reducing the overall signal-generated Ca(2+) influx without altering the signal resulting from voltage-dependent Ca(2+) entry. Notably neither Ca(2+) entry via voltage-dependent Ca(2+) channels nor Ca(2+) release via IP(3)Rs alters mitochondrial location or mitochondrial membrane potential in intact smooth muscle cells. Collectively these results demonstrate that activation of voltage-dependent Ca(2+) channels drives Ca(2+) entry, which subsequently triggers Ca(2+) release from the internal store in smooth muscle cells. Mitochondria selectively regulate this process by modulating IP(3)R-mediated amplification of Ca(2+) signals, ensuring that different cellular responses are precisely controlled. KEY POINTS: In smooth muscle Ca(2)⁺ entry via voltage-dependent channels produces a uniform Ca(2)⁺ increase, enabling co-ordinated contraction in each cell. Certain functions, however, require large, pulsatile Ca(2)⁺ changes rather than a uniform increase. Using advanced imaging in intact arteries, we discovered that voltage-dependent Ca(2)⁺ entry triggers internal store Ca(2)⁺ release via IP₃ receptors, generating repetitive Ca(2)⁺ 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(2+) signal. These findings demonstrate how voltage-dependent Ca(2)⁺ entry supports both co-ordinated contraction and pulsatile Ca(2)⁺-driven biological responses.