Ero1α Regulates Ca 2+ Fluxes at the Endoplasmic Reticulum–Mitochondria Interface (MAM)

140

152

SummaryThe reducing power of glutathione, expressed by its reduction potential E GSH , is an accepted measure for redox conditions in a given cell compartment. In the endoplasmic reticulum (ER), E GSH is less reducing than elsewhere in the cell. However, attempts to determine E GSH (ER) have been inconsistent and based on ineligible assumptions. Using a codon-optimized and evidently glutathione-specific glutaredoxin-coupled redox-sensitive green fluorescent protein (roGFP) variant, we determined E GSH (ER) in HeLa cells as 220864 mV (at pH 7.0). At variance with existing models, this is not oxidizing enough to maintain the known redox state of protein disulfide isomerase family enzymes. Live-cell microscopy confirmed ER hypo-oxidation upon inhibition of ER Ca 2+ import. Conversely, stressing the ER with a glycosylation inhibitor did not lead to more reducing conditions, as reported for yeast. These results, which for the first time establish the oxidative capacity of glutathione in the ER, illustrate a context-dependent interplay between ER stress and E GSH (ER). The reported development of ER-localized E GSH sensors will enable more targeted in vivo redox analyses in ERrelated disorders.

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

Birk¹,

Meyer²,

Aller³

et al. 2013

140

152

“…In addition to its role in disulfide bond formation, Ero1a is a positive regulator of IP 3 R. Accordingly, IP 3 R-dependent Ca 2+ flux to the cytosol and mitochondria is stimulated by induction of Ero1a (Anelli et al, 2012;Li et al, 2009). Increased cytosolic Ca 2+ levels feed into the JNK pathway through Ca 2+ /calmodulindependent protein kinase II (CaMKII) and thereby lead to augmented ROS production through NOX2 (also known as CYBB) or NOX4, which in turn leads to oxidative stress and positive-feedback regulation of CHOP through double-stranded RNA-dependent protein kinase (PKR; also known as EIF2AK2) (Li et al, 2010a;Pedruzzi et al, 2004) (Figs 2 and 3).…”

Section: Er Stress Can Increase Ros Generationmentioning

confidence: 99%

“…upregulation of Ero1a potentiates IP 3 -induced Ca 2+ release (Anelli et al, 2012;Kiviluoto et al, 2013;Li et al, 2009). Furthermore, the degradation of IP 3 Rs and RyRs is inhibited during ER stress (Belal et al, 2012) and the ER membrane protein s-1 receptor dissociates from BiP to chaperone and stabilize type 3 IP 3 R at MAM (Hayashi and Su, 2007).…”

Section: The Er-stress-mitochondrial Signaling Axismentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

154

137

In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

“…Mitochondria generate ROS through the electron transport chain, whereas the oxidative folding machinery in the ER produces H 2 O 2 and includes ERO1, which is localized to the MAM Anelli et al, 2012). ROS can change the activity of both ER and mitochondrial Ca 2+ transport mechanisms, and ROS production itself is also affected by Ca 2+ (Brookes et al, 2004).…”

Section: Local Signalingmentioning

confidence: 99%

Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle – pivotal roles in Ca2+ and reactive oxygen species signaling

Eisner

Csordás

Hajnóczky

2013

186

174

SummaryMitochondria are strategically and dynamically positioned in the cell to spatially coordinate ATP production with energy needs and to allow the local exchange of material with other organelles. Interactions of mitochondria with the sarco-endoplasmic reticulum (SR/ER) have been receiving much attention owing to emerging evidence on the role these sites have in cell signaling, dynamics and biosynthetic pathways. One of the most important physiological and pathophysiological paradigms for SR/ER-mitochondria interactions is in cardiac and skeletal muscle. The contractile activity of these tissues has to be matched by mitochondrial ATP generation that is achieved, at least in part, by propagation of Ca 2+ signals from SR to mitochondria. However, the muscle has a highly ordered structure, providing only limited opportunity for mitochondrial dynamics and interorganellar interactions. This Commentary focuses on the latest advances in the structure, function and disease relevance of the communication between SR/ER and mitochondria in muscle. In particular, we discuss the recent demonstration of SR/ER-mitochondria tethers that are formed by multiple proteins, and local Ca 2+ transfer between SR/ER and mitochondria.