Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

Abstract

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER-mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders.

Fig. 1

Major physiological functions of the endoplasmic reticulum and their perturbations cause ER stress and activate the unfolded protein response. The endoplasmic reticulum (ER) fulfills several important processes within the cell. Proteins of the secretory pathway are synthesized and folded in the oxidative environment of the ER lumen. Properly folded proteins can be distributed to other subcellular compartments through vesicular traffic. Terminally misfolded proteins are exported to the cytoplasm where they are degraded by the proteasome. The ER plays a major role in lipid biosynthesis and calcium handling, the latter being a primary messenger for communication between ER and mitochondria. The ER serves as a homeostatic stress sensor, activating the adaptive unfolded protein response (UPR) to restore the folding capacity of the ER.

Fig. 2

Early phases of endoplasmic reticulum (ER) stress trigger an increase in mitochondrial metabolism which depends critically upon organelle coupling and Ca²⁺ transfer. The onset of ER stress is characterized by a redistribution of the reticular and mitochondrial networks towards the perinuclear region and a microtubule-dependent increase in their points of connection. Physical coupling is achieved by anchoring proteins, such as mitofusin 2 (Mfn2). This interaction allows an increased Ca²⁺ transfer from ER to mitochondria, which enhances mitochondrial bioenergetics and ATP production. However, if stress persists, this response promotes mitochondrial collapse and triggers apoptotic cell death.