Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism

Abstract

The past decade has seen the emergence of endoplasmic reticulum (ER) chaperones as key determinants of contact formation between mitochondria and the ER on the mitochondria-associated membrane (MAM). Despite the known roles of ER–mitochondria tethering factors like PACS-2 and mitofusin-2, it is not yet entirely clear how they mechanistically interact with the ER environment to determine mitochondrial metabolism. In this article, we review the mechanisms used to communicate ER redox and folding conditions to the mitochondria, presumably with the goal of controlling mitochondrial metabolism at the Krebs cycle and at the electron transport chain, leading to oxidative phosphorylation (OXPHOS). To achieve this goal, redox nanodomains in the ER and the interorganellar cleft influence the activities of ER chaperones and Ca2+-handling proteins to signal to mitochondria. This mechanism, based on ER chaperones like calnexin and ER oxidoreductases like Ero1α, controls reactive oxygen production within the ER, which can chemically modify the proteins controlling ER–mitochondria tethering, or mitochondrial membrane dynamics. It can also lead to the expression of apoptotic or metabolic transcription factors. The link between mitochondrial metabolism and ER homeostasis is evident from the specific functions of mitochondria–ER contact site (MERC)-localized Ire1 and PERK. These functions allow these two transmembrane proteins to act as mitochondria-preserving guardians, a function that is apparently unrelated to their functions in the unfolded protein response (UPR). In scenarios where ER stress cannot be resolved via the activation of mitochondrial OXPHOS, MAM-localized autophagosome formation acts to remove defective portions of the ER. ER chaperones such as calnexin are again critical regulators of this MERC readout.

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

“…These data as well as the deficit of mitochondria in both microglia and in oligodendrocytes suggest that the damage and deficit of mitochondria in microglia and in oligodendrocytes may be crucial in the disturbance of microglial and oligodendrocyte metabolism in schizophrenia, especially in the SPPS subgroup, during acute state of disease. Mitochondria play a key role in cellular energy potential, calcium buffering, production of reactive oxygen species (ROS), they participate in regulation of apoptosis (42,43). The deficits of mitochondria found in the present study is consistent with alterations in mitochondrial ultrastructure and number (13)(14)(15)44), energy metabolism and oxidative stress, including the PFC (45)(46)(47).…”

“…Thus, mitochondria abnormalities found in the present study are consistent with the alterations in mitochondrial energy metabolism, oxidative stress and neuroinflammation in schizophrenia, including the PFC. Mitochondria have contacts with endoplasmic reticulum (ER), and Ca 2+ flux from the ER to mitochondria supports the Krebs cycle (43). Interestingly, some evidence suggests microglial intracellular Ca 2+ signaling as a target of antipsychotic effects for the treatment of schizophrenia (58).…”

“…Interestingly, some evidence suggests microglial intracellular Ca 2+ signaling as a target of antipsychotic effects for the treatment of schizophrenia (58). Stressors disturb ER homeostasis, and the misfolded proteins may induce ER stress (43). In mammals, several viruses, invasive bacteria and parasites induce ER stress responses (59).…”

Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells

“…Contribution of PERK/JNK to K-Ras-mediated cancer metabolism and cell cycle progression is suggested for further study. ER stress is triggered by a disruption in ER function called the unfolded protein response (UPR), and there are three signaling pathways of eukaryotic cells initiated by ER stress sensors including PERK, IRE1, and ATF6 [53]. PERK activation may phosphorylate eIF2α and activate the downstream transcriptional factor CHOP, leading to initiation of the mitochondrial pathway of apoptosis, including activation of caspases-9 and -3.…”

Modeling the transport of nuclear proteins along single skeletal muscle cells

“…S2). The results from the untargeted fluorescent protein suggest that diffusion alone, without organelle localization, is insufficient to create gradients within myotubes, while the results of the two fluorescent proteins targeted to the mitochondria imply that organelle dynamics (e.g., transport, fusion and fission) can partially resolve gradients that are initially created by organelle targeting, irrespective of the diffusion coefficient of the fluorescent protein (15,16).…”