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

Pál Pacher, Kumar Sharma, György Csordás, Yanqing Zhu, György Hajnóczky

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-β alters cytosolic [Ca 2+] ([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-β on the ER-mitochondrial Ca2+ transfer, we first studied the [Ca2+]c and mitochondrial matrix Ca 2+ ([Ca2+]m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-β 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 [Ca 2+]c signal and was delayed. In permeabilized cells, TGF-β 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-β. Also, TGF-β 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-β-treated PGASMC. Thus, TGF-β 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 Ca 2+ release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophysiology associated with TGF-β production.

Original languageEnglish (US)
Pages (from-to)F1303-F1312
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

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Keywords

  • Angiotensin II
  • IP receptor
  • Mitochondria
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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