title: Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-beta.
abstract: Transforming growth factor-beta (TGF-beta) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-beta alters cytosolic [Ca2+] ([Ca2+]c) signals, which in some cases may result from the downregulation of the IP3 receptor Ca2+ channels (IP3R). Ca2+ released by IP3Rs is effectively transferred from endoplasmic reticulum (ER) to the mitochondria to stimulate ATP production and to allow feedback control of the Ca2+ mobilization. To assess the effect of TGF-beta on the ER-mitochondrial Ca2+ transfer, we first studied the [Ca2+]c and mitochondrial matrix Ca2+ ([Ca2+]m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-beta pretreatment (24 h) decreased both the [Ca2+]c and [Ca2+]m responses evoked by angiotensin II or endothelin. Strikingly, the [Ca2+]m signal was more depressed than the [Ca2+]c signal and was delayed. In permeabilized cells, TGF-beta pretreatment attenuated the rate but not the magnitude of the IP(3)-induced [Ca2+]c rise, yet caused massive depression of the [Ca2+]m responses. ER Ca2+ storage and mitochondrial uptake of added Ca2+ were not affected by TGF-beta. Also, TGF-beta had no effect on mitochondrial distribution and on the ER-mitochondrial contacts assessed by two-photon NAD(P)H imaging and electron microscopy. Downregulation of both IP3R1 and IP3R3 was found in TGF-beta-treated PGASMC. Thus, TGF-beta causes uncoupling of mitochondria from the ER Ca2+ release. The sole source of this would be suppression of the IP3R-mediated Ca2+ efflux, indicating that the ER-mitochondrial Ca2+ transfer depends on the maximal rate of Ca2+ release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophysiology associated with TGF-beta production.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.forename: György
authors.initials: G
authors.lastname: Csordás
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016232:Endothelins / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000166:cytology; D007700:Kinetics; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D016232:Endothelins; D005456:Fluorescent Dyes; D006575:Heterocyclic Compounds, 3-Ring; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016212:Transforming Growth Factor beta; C068483:rhod-2; D000804:Angiotensin II; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium