scholarly journals SESN2 protects against denervated muscle atrophy through unfolded protein response and mitophagy

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Xiaofan Yang ◽  
Pingping Xue ◽  
Meng Yuan ◽  
Xiang Xu ◽  
Cheng Wang ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Muscle Atrophy ◽  
Critical Role ◽  
C2c12 Cells ◽  
Skeletal Muscle Atrophy ◽  
Denervated Muscle ◽  
Unfolded Protein ◽  
Sequestosome 1 ◽  
Protein Response

AbstractDenervation of skeletal muscles results in a rapid and programmed loss of muscle size and performance, termed muscle atrophy, which leads to a poor prognosis of clinical nerve repair. Previous researches considered this process a result of multiple factors, such as protein homeostasis disorder, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and apoptosis, while their intrinsic association remains to be explored. In this study, Sestrin2 (SESN2), a stress-inducible protein, was shown to act as a key protective signal involved in the crosstalk therein. SESN2 expression was induced in the gastrocnemius two weeks post denervation, which was accompanied by ERS, mitochondrial dysfunction, and apoptosis. Knockdown of SESN2 aggravated this situation and resulted in severer atrophy. Similar results were also found in rotenone-treated C2C12 cells. Furthermore, SESN2 was demonstrated to be induced by an ERS-activated transcription factor CCAAT-enhancer-binding protein beta (C/EBPβ). Once induced, SESN2 halted protein synthesis by inhibiting the mammalian target of rapamycin complex 1 (mTORC1), thereby attenuating ERS. Moreover, increased SESN2 activated the specific autophagic machinery and facilitated the aggregation of sequestosome 1 (SQSTM1, p62) on the mitochondrial surface, which promoted the clearance of damaged mitochondria through mitophagy. Collectively, the SESN2-mediated unfolded protein response (UPR) and mitophagy play a critical role in protecting against denervated muscle atrophy, which may provide novel insights into the mechanism of skeletal muscle atrophy following denervation.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

scholarly journals Cole Haynes: On the trail of mitochondrial dysfunction

2015 ◽  
Vol 208 (2) ◽  
pp. 140-141
Author(s):  
Kendall Powell
Keyword(s):  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Haynes tracks the mitochondrial unfolded protein response and its ramifications for cellular health.

scholarly journals ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 330-339 ◽  
Author(s):  
Olga V. Oskolkova ◽  
Taras Afonyushkin ◽  
Alexander Leitner ◽  
Elena von Schlieffen ◽  
Peter S. Gargalovic ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Target Genes ◽  
Critical Role ◽  
Close Relation ◽  
Individual Species ◽  
Oxidized Phospholipids ◽  
Vegf Mrna ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract We have shown previously that oxidized phospholipids (OxPLs), known to accumulate in atherosclerotic vessels, stimulate angiogenesis via induction of autocrine mediators, such as vascular endothelial growth factor (VEGF). We now address the pathways mediating up-regulation of VEGF in human endothelial cells treated with OxPLs. Analysis of structure-function relationship using individual species of OxPLs demonstrated a close relation between induction of VEGF and activation of the unfolded protein response (UPR). Inducers of UPR up-regulated VEGF, whereas inhibition of UPR by chemical chaperones or knock-down of cochaperone HTJ-1 inhibited elevation of VEGF mRNA induced by OxPLs. OxPLs induced protein expression of activating transcription factor-4 (ATF4), an important effector of UPR. Expression levels of VEGF in OxPL-treated cells strongly correlated with induction of the ATF4 target genes ATF3 and TRB3. Knocking down ATF4 was paralleled by loss of VEGF induction by OxPLs. Chromatin immunoprecipitation demonstrated that OxPLs stimulated binding of ATF4 to a regulatory site in the VEGFA gene. Taken together, these data characterize UPR and more specifically its ATF4 branch as an important mechanism mediating up-regulation of VEGF by OxPLs, and allow hypothesizing that the UPR cascade might play a role in pathologic angiogenesis in atherosclerotic plaques.

scholarly journals Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle

2020 ◽  
Vol 318 (4) ◽  
pp. R677-R690 ◽  
Author(s):  
Yuka Wakabayashi ◽  
Yuki Tamura ◽  
Karina Kouzaki ◽  
Naoki Kikuchi ◽  
Kenji Hiranuma ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Gastrocnemius Muscle ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Acetaldehyde Dehydrogenase ◽  
Unfolded Protein ◽  
Protein Response

Acetaldehyde dehydrogenase 2 (ALDH2) is an enzyme involved in redox homeostasis as well as the detoxification process in alcohol metabolism. Nearly 8% of the world’s population have an inactivating mutation in the ALDH2 gene. However, the expression patterns and specific functions of ALDH2 in skeletal muscles are still unclear. Herein, we report that ALDH2 is expressed in skeletal muscle and is localized to the mitochondrial fraction. Oxidative muscles had a higher amount of ALDH2 protein than glycolytic muscles. We next comprehensively investigated whether ALDH2 knockout in mice induces mitochondrial adaptations in gastrocnemius muscle (for example, content, enzymatic activity, respiratory function, supercomplex formation, and functional networking). We found that ALDH2 deficiency resulted in partial mitochondrial dysfunction in gastrocnemius muscle because it increased mitochondrial reactive oxygen species (ROS) emission (2′,7′-dichlorofluorescein and MitoSOX oxidation rate during respiration) and the frequency of regional mitochondrial depolarization. Moreover, we determined whether ALDH2 deficiency and the related mitochondrial dysfunction trigger mitochondrial stress and quality control responses in gastrocnemius muscle (for example, mitophagy markers, dynamics, and the unfolded protein response). We found that ALDH2 deficiency upregulated the mitochondrial serine protease Omi/HtrA2 (a marker of the activation of a branch of the mitochondrial unfolded protein response). In summary, ALDH2 deficiency leads to greater mitochondrial ROS production, but homeostasis can be maintained via an appropriate stress response.

scholarly journals The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 333 ◽  
Author(s):  
Alberto M. Martelli ◽  
Francesca Paganelli ◽  
Francesca Chiarini ◽  
Camilla Evangelisti ◽  
James A. McCubrey
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Critical Role ◽  
Cell Protein ◽  
Acute Leukemias ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Novel Therapeutic

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

scholarly journals Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

2021 ◽  
Vol 22 (20) ◽  
pp. 11049
Author(s):  
Lucie Crouzier ◽  
Morgane Denus ◽  
Elodie M. Richard ◽  
Amarande Tavernier ◽  
Camille Diez ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Mitochondrial Activity ◽  
Sigma 1 Receptor ◽  
Unfolded Protein ◽  
Sigma 1 ◽  
Protein Response ◽  
The Impact

The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca2+ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1rWT. The locomotion of the s1r+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R.

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