%0 Journal Article
%T ER-Mitochondria Crosstalk during Cerebral Ischemia: Molecular Chaperones and ER-Mitochondrial Calcium Transfer
%A Yi-Bing Ouyang
%A Rona G. Giffard
%J International Journal of Cell Biology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/493934
%X It is commonly believed that sustained elevations in the mitochondrial matrix Ca2+ concentration are a major feature of the intracellular cascade of lethal events during cerebral ischemia. The physical association between the endoplasmic reticulum (ER) and mitochondria, known as the mitochondria-associated ER membrane (MAM), enables highly efficient transmission of Ca2+ from the ER to mitochondria under both physiological and pathological conditions. Molecular chaperones are well known for their protective effects during cerebral ischemia. It has been demonstrated recently that many molecular chaperones coexist with MAM and regulate the MAM and thus Ca2+ concentration inside mitochondria. Here, we review recent research on cerebral ischemia and MAM, with a focus on molecular chaperones and ER-mitochondrial calcium transfer. 1. Introduction Stroke is one of the leading causes of death worldwide and a major cause of long-term disability [1]. Although many clinical trials have been completed in stroke patients, none of these have demonstrated protective efficacy except for thrombolysis [2, 3]. Suggested reasons for this failure include the complex interplay among multiple pathways (for review see [4¨C6]) including excitotoxicity, mitochondrial dysfunction, acidotoxicity, ionic imbalance, oxidative stress, and inflammation, which can all lead to cell death and irreversible tissue injury. A generally accepted cell death pathway after cerebral ischemia is mitochondrial permeability transition (MPT) pore opening (Figure 1(a)). Ischemia leads to energy deprivation and loss of ion homeostasis. As the cells are unable to maintain a negative membrane potential, they depolarize, leading to the opening of voltage-gated calcium channels and release of excitatory amino acids into the extracellular space [7]. This cascade of events leads to a massive entry of calcium and this increase in free cytosolic calcium is transmitted to the matrix of mitochondria by Ca2+ channels and exchangers located on the inner mitochondrial membrane. Recently ER stress was found to be one of the effects of excitotoxicity, that is, exposure to toxic levels of excitatory neurotransmitters, with release of Ca2+ from the ER via both ryanodine receptors and IP3R, with release from inositol trisphosphate receptors (IP3Rs) leading to mitochondrial Ca2+ overload and activation of apoptosis [8]. Excessive increases in matrix Ca2+ alter the permeability of mitochondria and finally open the MPT pore [9], causing the release of cytochrome c [10] and other proapoptotic factors into the cytoplasm. The
%U http://www.hindawi.com/journals/ijcb/2012/493934/