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.
Highlights
Close to 10 years ago, we proposed a tight regulatory connection between oxidative protein folding within the endoplasmic reticulum (ER) and mitochondrial oxidative phosphorylation (OXPHOS) [1]
Increasing evidence confirms that ER oxidative protein folding acts as a “canary in the coalmine”, whose constant working is monitored by ER chaperones and oxidoreductases to adjust demands of energy and determine their sources
The redox events occurring at ER–mitochondria contact sites have wide significance for cellular physiology, and for disease, since they determine the metabolic balance of energy generation
Summary
Close to 10 years ago, we proposed a tight regulatory connection between oxidative protein folding within the endoplasmic reticulum (ER) and mitochondrial oxidative phosphorylation (OXPHOS) [1]. The PDI family member P5 that can localize to mitochondria could maintain or even increase Krebs cycle activity under oxidative stress by sustaining the function of citrate synthase [101], a function that would suppress the release of cytochrome c and the generation of mitochondrial superoxide [102]. Ero1α and ERdj might have opposite significance for cellular metabolism [112] In contrast to this role focusing on Ca2+ uptake, Ero1α can oxidize and activate IP3 R, increasing Ca2+ release from the ER, likely dependent on its localization to MERCs [4,113].
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