摘要：SummaryThis study shows that multiple modes of mitochondrial stress generated by partial mtDNA depletion or cytochromecoxidase disruption cause ryanodine receptor channel (RyR) dysregulation, which instigates the release of Ca2+in the cytoplasm of C2C12 myoblasts and HCT116 carcinoma cells. We also observed a reciprocal downregulation of IP3R channel activity and reduced mitochondrial uptake of Ca2+. Ryanodine, an RyR antagonist, abrogated the mitochondrial stress-mediated increase in [Ca2+]cand the entire downstream signaling cascades of mitochondrial retrograde signaling. Interestingly, ryanodine also inhibited mitochondrial stress-induced invasive behavior in mtDNA-depleted C2C12 cells and HCT116 carcinoma cells. In addition, co-immunoprecipitation shows reduced FKBP12 protein binding to RyR channel proteins, suggesting the altered function of the Ca2+channel. These results document how the endoplasmic reticulum-associated RyR channels, in combination with inhibition of the mitochondrial uniporter system, modulate cellular Ca2+homeostasis and signaling under mitochondrial stress conditions.Graphical AbstractDisplay OmittedHighlights•Multiple types of mitochondrial stress induce the expression of RyR channel genes•Stress-induced RyR channels are leaky, causing the release of Ca2+in the cytosol•Mitochondrial stress also impairs Ca2+uptake through mitochondrial uniporter•RyR antagonists blocked Ca2+leak, downstream signaling, and target gene expressionBiological Sciences; Molecular Biology; Cell Biology
