Interactions of endoplasmic reticulum and mitochondria Ca(2+) stores with capacitative calcium entry.
Academic Article
Overview
abstract
Thiamine dependent enzymes are diminished in Alzheimer's disease (AD). Thiamine deficiency in vitro and in rodents is a useful model of this reduction. Thiamine interacts with cellular calcium stores. To directly test the relevance of the thiamine dependent changes to dynamic processes in AD, the interactions must be studied in cells from patients with AD. These studies employed fibroblasts. Mitochondrial dysfunction including reductions in thiamine dependent enzymes and abnormalities in calcium homeostasis and oxidative processes occur in fibroblasts from Alzheimer's Disease (AD) patients. Bombesin-releasable calcium stores (BRCS) from the endoplasmic reticulum (ER) are exaggerated in fibroblasts from patients with AD bearing a presenilin-1 (PS-1) mutation and in control fibroblasts treated with oxidants. ER calcium regulates calcium entry into the cell through capacitative calcium entry (CCE), which is reduced in fibroblasts and neurons from mice bearing PS-1 mutations. Under physiological conditions, mitochondria and ER play important and interactive roles in the regulation of Ca(2+) homeostasis. Thus, the interactions of mitochondria and oxidants with CCE were tested. Inhibition of ER Ca(2+)-ATPase by cyclopiazonic acid (CPA) stimulates CCE. CPA-induced CCE was diminished by inhibition of mitochondrial Ca(2+) export (-60%) or import (-40%). Different aspects of mitochondrial Ca(2+) coupled to CPA-induced-CCE were sensitive to select oxidants. The effects were very different when CCE was examined in the presence of InsP3, a physiological regulator of ER calcium release, and subsequent CCE. CCE under these conditions was only mildly reduced (20-25%) by inhibition of mitochondrial Ca(2+) export, and inhibition of mitochondrial Ca(2+) uptake exaggerated CCE (+53%). However, t-BHP reversed both abnormalities. The results suggest that in the presence of InsP3, mitochondria buffer the local Ca(2+) released from ER following rapid activation of InsP3R and serve as a negative feedback to the CCE. The results suggest that mitochondrial Ca(2+) modifies the depletion and refilling mechanism of ER Ca(2+) stores.
