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

摘要

Transforming growth factor-p (TGF-P) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-P alters cytosolic [Ca~(2+)] ([Ca~(2+)]_c) signals, which in some cases may result from the downregulation of the IP_3 receptor Ca~(2+) channels (IP3R). Ca~(2+) released by IP3Rs is effectively transferred from endoplasmic reticulum (ER) to the mitochondria to stimulate ATP production and to allow feedback control of the Ca~(2+) mobilization. To assess the effect of TGF-p on the ER-mitochondrial Ca~(2+) transfer, we first studied the [Ca~(2+)]_o and mitochondrial matrix Ca~(2+) ([Ca~(2+)]_m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-P pretreatment (24 h) decreased both the [Ca~(2+)]_c and [Ca~(2+)]_m responses evoked by angiotensin II or endothelin. Strikingly, the [Ca~(2+)]_m signal was more depressed than the [Ca~(2+)]_c signal and was delayed. In permeabilized cells, TGF-p pretreatment attenuated the rate but not the magnitude of the IP3-induced [Ca~(2+)]_c rise, yet caused massive depression of the [Ca~(2+)]_m responses. ER Ca~(2+) storage and mitochondrial uptake of added Ca~(2+) were not affected by TGF-p. Also, TGF-p 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-p-treated PGASMC. Thus, TGF-p causes uncoupling of mitochondria from the ER Ca~(2+) release. The sole source of this would be suppression of the IP3R-mediated Ca~(2+) efflux, indicating that the ER-mitochondrial Ca~(2+) transfer depends on the maximal rate of Ca~(2+) release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophys-iology associated with TGF-P production.