Heat shock protein 90beta1 is essential for polyunsaturated fatty acid-induced mitochondrial Ca2+ efflux.
Nonesterified fatty acids may influence mitochondrial function by alterations in gene expression, metabolism, and/or mitochondrial Ca(2+) ([Ca(2+)](m)) homeostasis. We have previously reported that polyunsaturated fatty acids induce Ca(2+) efflux from mitochondria, an action that may deplete [Ca(2+)](m) and thus contribute to nonesterified fatty acid-responsive mitochondrial dysfunction. Here we show that the chaperone protein heat shock protein 90 beta1 (hsp90beta1) is required for polyunsaturated fatty acid-induced mitochondrial Ca(2+) efflux (PIMCE). Retinoic acid induced differentiation of human teratocarcinoma NT2 cells in association with attenuation of PIMCE. Proteomic analysis of mitochondrial proteins revealed that hsp90beta1, among other proteins, was reduced in retinoic acid-differentiated cells. Blockade of PIMCE in NT2 cells by 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin, a known inhibitor of the chaperone activity of hsp90, and hsp90beta1 RNA interference demonstrated that hsp90beta1 is essential for PIMCE. We also show localization of hsp90beta1 in mitochondria by Western blot and immunofluorescence. Distinctive effects of inhibitors binding to the N or C terminus of hsp90 on PIMCE in isolated mitochondria suggested that the C terminus of hsp90beta1 plays a critical role in PIMCE.
Zhang
Hua
H
Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, Audie L. Murphy Division, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Li
Zhen-Hua
ZH
Zhang
Michael Q
MQ
Katz
Michael S
MS
Zhang
Bin-Xian
BX
D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D005231:Fatty Acids, Unsaturated / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D034622:RNA Interference; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D016227:Benzoquinones; D005231:Fatty Acids, Unsaturated; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D047029:Lactams, Macrocyclic; D024101:Mitochondrial Proteins; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D014212:Tretinoin; D002118:Calcium