Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-β

Pacher P, Sharma K, Csordas G, Zhu Y, Hajnoczky G. Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-beta. Am J Physiol Renal Physiol 295: F1303-F1312, 2008. First published July 23, 2008; doi:10.1152/ajprenal.90343.2008.-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 IP3-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.