The key chaperones and folding sensors in the ER include the peptide-binding proteins BiP and GRP94, the lectins calnexin and calreticulin, and the thiol-disulfide oxidoreductases such as protein disulfide isomerase (PDI) and Erp57. Although the amino acid sequence of the protein determines many of these precise processes, numerous proteins, including chaperones and enzymes, aid in proper protein biosynthesis and folding. These cellular processes are initiated when nascent polypeptide chains emerge in ER lumen, where posttranslational modifications such as N-linked glycosylation, and intra- and intermolecular disulfide bond formation facilitate the folding of polypeptides to form specific tertiary and quaternary structures for proper protein function ( Molinari 2007). Newly synthesized proteins require proper folding within the ER lumen prior to trafficking to specific destinations in the cell. In addition, this organelle is also the site of cholesterol and steroid biosynthesis, lipid biosynthesis, assembly of core-asparagine linked oligosaccharides, and membrane and secreted protein biosynthesis.

The ER is an elaborate membranous network present in all eukaryotic cells and responsible for many homeostatic responses that include folding and maturation of newly synthesized secretory and transmembrane proteins ( Kleizen and Braakman 2004). We discuss the signaling/communication between the ER and mitochondria and focus on the role of the mitochondrial permeability transition pore in these complex processes. Regulated Ca 2+ transfer from the ER to the mitochondria is important in maintaining control of prosurvival/prodeath pathways. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes ) essential to maintain cellular homeostasis and determine cell fate under various pathophysiological conditions. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. If protein misfolding is not resolved, the UPR triggers apoptotic cascades. UPR provides an adaptive mechanism by which cells can augment protein folding and processing capacities of the ER. Unfolded protein response (UPR) is a highly regulated intracellular signaling pathway that prevents accumulation of misfolded proteins in the ER lumen. Properly folded proteins traffic from the ER to the Golgi apparatus misfolded proteins are targeted to degradation. Proteins are translocated into ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to assist in proper folding. The endoplasmic reticulum (ER) is the primary site for synthesis and folding of secreted and membrane-bound proteins.

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