title: Polyunsaturated fatty acids mobilize intracellular Ca2+ in NT2 human teratocarcinoma cells by causing release of Ca2+ from mitochondria.
abstract: 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 function found in diverse diseases. One of the most important regulators of mitochondrial function is mitochondrial Ca(2+) ([Ca(2+)](m)), which fluctuates in coordination with intracellular Ca(2+) ([Ca(2+)](i)). Polyunsaturated FA (PUFA) have been shown to cause [Ca(2+)](i) mobilization albeit by unknown mechanisms. We have found that PUFA but not monounsaturated or saturated FA cause [Ca(2+)](i) mobilization in NT2 human teratocarcinoma cells. Unlike the [Ca(2+)](i) response to the muscarinic G protein-coupled receptor agonist carbachol, PUFA-mediated [Ca(2+)](i) mobilization in NT2 cells is independent of phospholipase C and inositol-1,4,5-trisphospate (IP(3)) receptor activation, as well as IP(3)-sensitive internal Ca(2+) stores. Furthermore, PUFA-mediated [Ca(2+)](i) mobilization is inhibited by the mitochondria uncoupler carboxyl cyanide m-chlorophenylhydrozone. Direct measurements of [Ca(2+)](m) with X-rhod-1 and (45)Ca(2+) indicate that PUFA induce Ca(2+) efflux from mitochondria. Further studies show that ruthenium red, an inhibitor of the mitochondrial Ca(2+) uniporter, blocks PUFA-induced Ca(2+) efflux from mitochondria, whereas inhibitors of the mitochondrial permeability transition pore cyclosporin A and bongkrekic acid have no effect. Thus PUFA-gated Ca(2+) release from mitochondria, possibly via the Ca(2+) uniporter, appears to be the underlying mechanism for PUFA-induced [Ca(2+)](i) mobilization in NT2 cells.
authors.affiliation: Geriatric Research, Education and Clinical Center (182), South Texas Veterans Health Care System, Audie L. Murphy Division, 7400 Merton Minter Blvd., San Antonio, TX 78229, USA. zhangb2@uthscsa.edu
authors.forename: Bin-Xian
authors.initials: BX
authors.lastname: Zhang
authors.forename: Xiuye
authors.initials: X
authors.lastname: Ma
authors.forename: Wanke
authors.initials: W
authors.lastname: Zhang
authors.forename: Chih-Ko
authors.initials: CK
authors.lastname: Yeh
authors.forename: Alan
authors.initials: A
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Sprague
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.forename: Michael S
authors.initials: MS
authors.lastname: Katz
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018243:Teratocarcinoma / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D002118:Calcium