부산대학교 도서관

In a variety of disorders, overaccumulation of lipid in nonadipose tissues, including the heart, skeletal muscle, kidney, and liver, is associated with deterioration of normal organ function, and is accompanied by excessive plasma and cellular levels of free fatty acids (FA). Increased concentrations of FA may lead to defects in mitochondrial fnnction found in diverse diseases. One of the most important regulators of mitochondrial function is mitochondrial [Ca.sup.2+] ([[Ca.sup.2+]]m), which fluctuates in coordination with intracellular [Ca.sup.2+] ([[Ca.sup.2+]]0. Polyunsaturated FA (PUFA) have been shown to cause [[Ca.sup.2+]]i mobilization albeit by unknown mechanisms. We have found that PUFA but not monounsaturated or saturated FA cause [[Ca.sup.2+]]i mobilization in NT2 human teratocarcinoma cells. Unlike the [[Ca.sup.2+]]i response to the muscarinic G protein-coupled receptor agonist carbachol, PUFA-mediated [[Ca.sup.2+]]i mobilization in NT2 cells is independent of phospholipase C and inositol-l,4,5-trisphospate (I[P.sub.3]) receptor activation, as well as I[P.sub.3]-sensitive internal [Ca.sup.2+] stores. Furthermore, PUFA-mediated [[Ca.sup.2+]]i mobilization is inhibited by the mitochondria uncoupler carboxyl cyanide m-chlorophenylhydrozone. Direct measurements of [[Ca.sup.2+]]m with X-rhod-1 and [sup.45][Ca.sup.2+] indicate that PUFA induce [Ca.sup.2+] efflux from mitochondria. Further studies show that ruthenium red, an inhibitor of the mitochondrial [Ca.sup.2+] uniporter, blocks PUFA-induced [Ca.sup.2+] efflux from mitochondria, whereas inhibitors of the mitochondrial permeability transition pore cyclosporin A and bongkrekic acid have no effect. Thus PUFA-gated [Ca.sup.2+] release from mitochondria, possibly via the [Ca.sup.2+] uniporter, appears to be the underlying mechanism for PUFA-induced [[Ca.sup.2+]]i mobilization in NT2 cells. arachidonic acid; mitochondrial [Ca.sup.2+] uniporter; G protein- coupled receptor; I[P.sub.3] receptor