The unfolded protein response: At the intersection between endoplasmic reticulum function and mitochondrial bioenergetics

Abstract

Endoplasmic reticulum (ER) to mitochondria communication has emerged in recent years as a signaling hub regulating cellular physiology with a relevant contribution to diseases including cancer and neurodegeneration. This functional integration is exerted through discrete interorganelle structures known as mitochondria-associated membranes (MAMs). At these domains, ER/mitochondria physically associate to dynamically adjust metabolic demands and the response to stress stimuli. Here, we provide a focused overview of how the ER shapes the function of the mitochondria, giving a special emphasis to the significance of local signaling of the unfolded protein response at MAMs. The implications to cell fate control and the progression of cancer are also discussed. Cellular organelles are no longer conceived as isolated entities with defined and unique functions, but as dynamic signaling nodes, where a single organelle may engage and influence the functioning of several cellular compartments and processes. Interorganelle interactions are facilitated by specialized structures that tie them together structurally and functionally. Mitochondria-associated membranes (MAMs) are subdomains that bring the endoplasmic reticulum (ER) and mitochondria into close proximity, enabling a complex cross talk (1). This physical association shapes mitochondrial morphology and dynamics (2), in addition to participate in the response to various stress stimuli, modulating metabolism, redox control, and apoptosis. The ER is the primary site where transmembrane and secretory proteins are folded; in addition to operate as the main intracellular calcium reservoir and a site of lipid biosynthesis. Abnormal accumulation of misfolded proteins within the ER lumen may result in the loss of proteostasis, a condition referred to as ER stress (3, 4). ER stress is triggered by physiological demands including high secretory activity, in addition to pathological conditions that may perturb protein folding and maturation, calcium homeostasis, redox balance, among other events. Under ER stress the unfolded protein response (UPR) is engaged, operating as a dynamic signaling network that enforces adaptive programs to restore proteostasis by reducing the load of unfolded proteins through the upregulation of genes involved in almost every aspect of the secretory pathway (5). However, if ER homeostasis cannot be restored, the UPR switches its signaling toward a proapoptotic mode to eliminate irreversibly damaged cells. Thus, the UPR is a central adjustor to control cell fate under ER stress, contributing to diverse pathological conditions including cancer, neurodegeneration, and diabetes, among others (6).