Cell Death and Survival Through the Endoplasmic Reticulum- Mitochondrial Axis

Abstract

The endoplasmic reticulum has a central role in biosynthesis of a variety of proteins and lipids. Mitochondria generate ATP, synthesize and process numerous metabolites, and are key regulators of cell death. The architectures of endoplasmic reticulum and mitochondria change continually via the process of membrane fusion, fission, elongation, degradation, and renewal. These structural changes correlate with important changes in organellar function. Both organelles are capable of moving along the cytoskeleton, thus changing their cellular distribution. Numerous studies have demonstrated coordination and communication between mitochondria and endoplasmic reticulum. A focal point for these interactions is a zone of close contact between them known as the mitochondrial-associated endoplasmic reticulum membrane (MAM), which serves as a signaling juncture that facilitates calcium and lipid transfer between organelles. Here we review the emerging data on how communication between endoplasmic reticulum and mitochondria can modulate organelle function and determine cellular fate. KeywordsCell death; endoplasmic reticulum; metabolism; mitochondria CONFLICT OF INTERESTThe authors confirm that this article content has no conflicts of interest. NIH Public Access Author ManuscriptCurr Mol Med. Author manuscript; available in PMC 2014 July 21. Published in final edited form as:Curr Mol Med. 2013 February ; 13(2): 317-329. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ORGANELLE FUNCTIONThe endoplasmic reticulum (ER) is an organelle whose primary function is protein synthesis and folding [1]. One third of cellular proteins are synthesized by ER-associated ribosomes, particularly those destined for secretion [2]. In the ER lumen, nascent polypeptides are modified with N-linked glycans and made accessible to proteins involved in proper protein folding and quality control [3,4]. In addition, the ER is the main site for biosynthesis of a variety of lipids such as phospholipids, cholesterol, and ceramides, which are transported to other organelles and cellular membranes via vesicles of the secretory pathway [5].ER is composed of a series of continuous membranous structures that are organized into subdomains that include the rough ER, smooth ER, transitional ER and the nuclear envelope [6]. The architecture of the ER changes continually according to cellular demand through the processes of fusion, fission, elongation and membrane degradation [6]. Structural differences correlate with differences in ER function [6]. The rough ER is mainly laminal and associated with polyribosomes for protein synthesis. The smooth ER is primarily composed of tubular structures. This is the site of phospholipid biosynthesis and is the chief point of contact with other organelles [6]. Changes in ER membrane curvature and structure are facilitated by several proteins, including GTPases and reticulons [6]. For a detailed view of ER structure and related processes, readers are referred to a recent excellent review by Park ...

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

“…Most catabolic pathways can produce NADH, and NADH is the primary electron donor in the electron transport chain (ETC) (Bravo-Sagua et al, 2013). Elevated NADH levels indicate that the catabolism in muscle has been enhanced and can facilitate the ETC process, which can further cause oxidative stress (Kussmaul and Hirst, 2006).…”

“…Approximately 20% of the outer mitochondrial membrane has close contact with the ER, which is also called the mitochondrial-associated ER membrane (Bravo-Sagua et al, 2013). Previously study has demonstrated that there is extensive communication and coordination between the ER and mitochondria (Perreault et al, 2009).…”

Redox Regulation of Store-Operated Ca2+Entry

“…Local Ca 2 + gradients are maintained around Ca 2 + entry or Ca 2 + release sites by the high concentration of cytosolic Ca 2 + -binding proteins that prevent the rapid diffusion of Ca 2 + ions within the cytosol, by the active extrusion and sequestration of the incoming Ca 2 + ions by PM Ca 2 + ATPases (PMCA) and SR/ER Ca 2 + ATPases (SERCA), and by Ca 2 + sequestration by neighboring mitochondria (166,174). The spatial coordination of Ca 2 + microdomains largely relies on the generation of membrane contact sites between the ER and the PM and between the ER and mitochondria, which act as intracellular signaling platforms to ensure the coordinated activities of Ca 2 + channels, pumps, and exchangers while favoring the spatial confinement of Ca 2 + signals (24,77). A precise spatial control of intracellular reactive oxygen species (ROS) generation may also be important for cellular functions because appropriate concentrations of ROS are required at specific cellular locations to control processes such as protein folding within the ER and bacterial killing within phagosomes.…”

“…In addition, Ca 2 + signals dynamically regulate the mitochondrial proton gradient (152), an important bioenergetic parameter that drives the electroneutral fluxes of substrates, metabolites, and ions required for mitochondrial respiration and volume homeostasis (150). The transfer of Ca 2 + between the ER and mitochondria occurs at membrane contact sites known as mitochondria-associated ER membranes (MAMs), a subdomain of the ER with distinct biochemical properties linked to mitochondria by protein tethers (24,77,164). In yeast, members of ER-Mitochondria Encounter Structure (ERMES) complex act as tethers and mediate the interorganellar interaction (77,97).…”

Characterisation of bilirubin metabolic pathway in hepatic mitochondria

“…Unfolded proteins can accumulate as a result of the oxidising condition, leaking Ca 2+ from lumen into cytosol, and increase ROS production in mitochondria (Leem and Koh, 2012;Bravo-Sagua et al, 2013). This in turn activates adaptive unfolded protein response (UPR) to restore protein folding and ER homeostasis.…”