bims-unfpre 2025-04-06 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–04–06
seven papers selected by
Susan Logue, University of Manitoba

Hyperoxia-induced senescence in fetal airway smooth muscle cells: Role of mitochondrial reactive oxygen species and endoplasmic reticulum stress.
Mettl3 deficiency leads to impaired insulin secretion via regulating Ire1a of mature β-cells in mice.
Akt mitigates ER stress-instigated cardiac dysfunction via regulation of ferroptosis and mitochondrial integrity in a DHODH-dependent manner.
Ferroptosis contributed to endoplasmic reticulum stress in preterm birth by targeting LHX1 and IRE-1.
Redox regulation of lung endothelial PERK, unfolded protein response (UPR) and proliferation via NOX1: Targeted inhibition as a potential therapy for PAH.
Plant ubiquitin E2 enzymes UBC32, UBC33, and UBC34 are involved in ERAD and function in host stress tolerance.
Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.

Am J Physiol Lung Cell Mol Physiol. 2025 Apr 04.

Hyperoxia-induced senescence in fetal airway smooth muscle cells: Role of mitochondrial reactive oxygen species and endoplasmic reticulum stress.

M L Koloko Ngassie, Michael A Thompson, Benjamin B Roos, Savita Ayyalasomayajula, Anthony B Lagnado, João F Passos, Christina M Pabelick, Y S Prakash.

  Premature infants are at higher risk for developing chronic lung diseases especially following supplemental oxygen (hyperoxia) in early life. We previously demonstrated that moderate hyperoxia (<60% O2) induces cellular senescence in fetal airway smooth muscle cells (fASM) and fibroblasts. However, the mechanisms underlying O2-induced senescence are still under investigation. In this study we investigated the role of endoplasmic reticulum (ER) stress and mitochondrial dysfunction, using fASM cells exposed to 21% (normoxia) vs. ~50% O2 (hyperoxia). Normoxia or hyperoxia-exposed fASM were treated with the ER stress inhibitor salubrinal [12.5 μM], the antioxidant MitoQ [100 nM] or the mitochondrial fission inhibitor Mdivi-1 [10 μM]. Samples were harvested at day 2, 3 and 7 and analyzed for markers of senescence, oxidative stress, ER stress response and mitochondrial dynamics using protein analysis and fluorescence microscopy. Hyperoxia enhanced senescence, upregulating multiple markers of DNA damage in particular, cyclin dependent cell cycle regulator p21, cytosolic and mitochondrial reactive oxygen species (ROS) levels, mitochondria fragmentation and anti- apoptosis Bcl-xL, while downregulating the proliferation marker Ki-67. Hyperoxia also activated all three ER stress pathways. However, the level of p21 and/or Bcl-xL was decreased in hyperoxia-exposed cells treated with the ER stress inhibitor salubrinal or the antioxidant MitoQ, but not the fission inhibitor Mdivi-1. These findings highlight the role of mitochondrial ROS and ER stress in hyperoxia-induced senescence of fASM and suggest that via mitochondrial targeted antioxidants and/or inhibitors of ER stress pathways can blunt the detrimental effects of hyperoxia in developing lung.

Keywords:  DNA damage; ER stress response; Oxidative stress; cellular senescence; mitochondria morphology

DOI:  https://doi.org/10.1152/ajplung.00348.2024
Sci Rep. 2025 Mar 29. 15(1): 10835

Mettl3 deficiency leads to impaired insulin secretion via regulating Ire1a of mature β-cells in mice.

Xu Zhang, Aijing Shan, Jie Chen, Yanan Cao, Xiuli Jiang.

  The modification of N6-methyladenosine (m6A) influences the translation and stability of transcripts, allowing for the coordination of gene regulation during cell state maintenance and transition. Deregulation of components in the m6A regulatory network is associated with glucose homeostasis and development of diabetes. In this study, we investigated the functional role of Mettl3, which is the key component of the m6A methyltransferase complex, in regulating β-cell identity and function in two pancreatic β-cell-specific Mettl3 knockout mouse models. The glucose metabolic phenotype, β-cell proliferation, islet architecture and insulin secretion were analyzed in vivo. We next analyzed the expression levels of genes associated with endoplasmic reticulum (ER) stress in the Mettl3 ablated islets. MeRIP-qPCR was applied to detect the m6A modification enrichment of Ire1α mRNA. Adenovirus-mediated Mettl3 infection was performed on islets to explore the effect of Mettl3 overexpression on ER stress and insulin secretion. Our results showed that Mettl3 deficiency led to loss of β-cell identity and impaired insulin secretion in mice. Depletion of Mettl3 verified the m6A modification in Ire1α and consequently induced ER stress in islet cells. Mettl3 overexpression in islets could alleviate ER stress and improve the insulin secretion capacity. Our findings demonstrated that Mettl3 was an important regulator of ER stress and insulin secretion in mouse pancreatic β-cells.

Keywords:  ER stress; Insulin secretion; Ire1α; Mettl3; Pancreatic β-cell; m6A methyltransferase

DOI:  https://doi.org/10.1038/s41598-025-93799-4
Life Sci. 2025 Mar 29. pii: S0024-3205(25)00225-5. [Epub ahead of print]371 123591

Akt mitigates ER stress-instigated cardiac dysfunction via regulation of ferroptosis and mitochondrial integrity in a DHODH-dependent manner.

Na Zhou, Li Ma, Wanting Shi, Russel J Reiter, Jie Lin, Yingmei Zhang, Dandan Hu, Jun Ren, Kaishou Xu.

  ER stress evokes various types of cell death and myocardial dysfunction. This study aimed to discern the involvement of ferroptosis in chronic Akt activation-offered benefit, if any, against ER stress-triggered cardiac remodeling and contractile anomalies. Cardiac-selective expression of active mutant of Akt (AktOE) and wild-type (WT) mice were challenged with the ER stress instigator tunicamycin (1 mg/kg, 48 h) prior to assessment of cardiac morphology and function. Tunicamycin insult prompted cardiac remodeling (interstitial fibrosis), deranged echocardiographic (higher LVESD, dropped ejection fraction and fractional shortening), cardiomyocyte mechanical and intracellular Ca2+ features alongside mitochondrial injury (collapsed mitochondrial membrane potential and ultrastructural change), oxidative stress, compromised Akt-GSK3β signaling, ER stress (upregulated GRP78 and Gadd153), carbonyl formation, apoptosis and ferroptosis (decreased GPX4, SLC7A11). Intriguingly, tunicamycin-evoked anomalies (except GRP78 and Gadd153) were abrogated by Akt activation. Chronic Akt activation negated tunicamycin-induced downregulation of ferric flavin enzyme dihydroorotate dehydrogenase (DHODH), which catalyzes the fourth step of pyrimidine ab initio biosynthesis, and conversion of dihydroorotic acid to orotate. ER stress-induced myocardial anomalies were reversed by the newly identified PI3K activator triptolide, DHODH activator menaquinone-4 and pyrimidine booster coenzyme Q. In vitro experiment revealed that Akt activation- or triptolide-evoked beneficial responses against tunicamycin-induced cardiomyocyte anomalies were cancelled off by DHODH inhibitor BAY2402234 or ferroptosis inducer erastin. These findings support that chronic Akt activation rescues ER stress-evoked myocardial derangements through DHODH-dependent control of ferroptosis and mitochondrial homeostasis.

Keywords:  Akt; DHODH; ER stress; Ferroptosis; Mitochondria

DOI:  https://doi.org/10.1016/j.lfs.2025.123591
Cell Signal. 2025 Mar 27. pii: S0898-6568(25)00190-1. [Epub ahead of print]132 111777

Ferroptosis contributed to endoplasmic reticulum stress in preterm birth by targeting LHX1 and IRE-1.

Liyin Qiu, Hui Liu, Shali Chen, Yiting Wu, Jianying Yan.

  Preterm birth (PTB) significantly contributed to neonatal mortality, emphasizing the need for a detailed understanding of its pathogenesis. This study aimed to explore the involvement of ferroptosis, an iron-dependent cell death process, in PTB and investigated the possible crosstalk with endoplasmic reticulum stress (ERS). First, we explored the occurrence of ferroptosis in placenta samples from PTB parturients. Then we established a ferroptosis cell model was established by subjecting trophoblast cells to hypoxia/reoxygenation (H/R), and found the ERS was induced in H/R exposed cells and was attenuated by ferroptosis inhibition using Fer-1, suggesting that ferroptosis could induce ERS. Meanwhile, we also induced ERS in trophoblast cells via tunicamycin (TM) treatment. Ferroptosis inhibition with Fer-1 alleviated TM-induced ER stress. TM treatment reduced trophoblast cell viability and migration while promoted apoptosis and autophagy, effects that were reversed by ferroptosis inhibition. Thus, targeting ferroptosis might help mitigate ER stress-related pathophysiological changes in PTB. Mechanically, we found two ERS mediators LIM homeobox 1 (LHX1)/Inositol-requiring enzyme 1 (IRE-1) were also upregulated in H/R treated cells. Silencing LHX1 or IRE-1 was demonstrated to reverse the H/R-induced ferroptosis. Additionally, rescue assays further revealed that LHX1 promoted ferroptosis by regulating IRE-1. In conclusion, ferroptosis contributed to ERS and was critically involved in PTB, highlighting the LHX1/IRE-1 axis as a promising therapeutic target for mitigating ferroptosis-related complications. These findings offered a foundation for innovative interventions in preterm birth.

Keywords:  Autophagy; Endoplasmic reticulum stress; Ferroptosis; IRE-1; LHX1; Preterm birth

DOI:  https://doi.org/10.1016/j.cellsig.2025.111777
Redox Biol. 2025 Feb 19. pii: S2213-2317(25)00067-9. [Epub ahead of print]82 103554

Redox regulation of lung endothelial PERK, unfolded protein response (UPR) and proliferation via NOX1: Targeted inhibition as a potential therapy for PAH.

Christian J Goossen, Alex Kufner, Christopher M Dustin, Imad Al Ghouleh, Shuai Yuan, Adam C Straub, John Sembrat, Jeffrey J Baust, Delphine Gomez, Damir Kračun, Patrick J Pagano.

   AIMS: Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary arterial hypertension (PAH) and NADPH oxidases (NOXs) as sources of ROS are implicated in the development of the disease. We previously showed that NOX isozyme 1 (NOX1)-derived ROS contributes to pulmonary vascular endothelial cell (EC) proliferation in response to PAH triggers in vitro. However, whether and how NOX1 is involved in PAH in vivo have not been explored nor has NOX1 been examined as a viable and effective therapeutic disease target.
METHODS AND RESULTS: Herein, infusion of mice exposed to Sugen/hypoxia (10 % O2) with a specific NOX1 inhibitor, NOXA1ds, delivered via osmotic minipumps (i.p.), significantly suppressed pathological changes in hemodynamic parameters characteristic of PAH. Furthermore, lungs of human patients with idiopathic PAH (iPAH) and exploratory RNA-seq analysis of hypoxic human pulmonary ECs, in which NOX1 was suppressed, were probed. The findings showed a clear indication of NOX1 in the promotion of both protein disulfide isomerase (PDI) and the unfolded protein response (UPR; in particular, the PERK arm of the pathway including eIF2α and ATF4) leading to proliferation. In aggregate, these results are consistent with a causal role for NOX1 in the development of mouse and human PAH and reveal a novel and mechanistic pathway by which NOX1 activates the UPR response during EC proliferation.
CONCLUSION: NOX1 promotes phenotypic changes in ECs that are pivotal to proliferation and PAH through activation of the UPR. Taken together, our results are consistent with selective inhibition of NOX1 as a novel modality for attenuating PAH.

Keywords:  Hypoxia; NADPH oxidases; NOX inhibitors; NOXA1ds; Pulmonary arterial hypertension; Unfolded protein response

DOI:  https://doi.org/10.1016/j.redox.2025.103554
BMC Plant Biol. 2025 Apr 02. 25(1): 412

Plant ubiquitin E2 enzymes UBC32, UBC33, and UBC34 are involved in ERAD and function in host stress tolerance.

Chaofeng Wang, Bangjun Zhou, Yi Zhang, Lirong Zeng.

   BACKGROUND: Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a critical component of the ER-mediated protein quality control (ERQC) system and plays a vital role in plant stress responses. However, the ubiquitination machinery underlying plant ERAD-particularly the ubiquitin-conjugating enzymes (E2s)-and their contributions to stress tolerance remain poorly understood.
RESULTS: In this study, we identified UBC32, UBC33, and UBC34 as ER-localized ubiquitin E2 enzymes involved in ERAD and demonstrated their roles in biotic and abiotic stress tolerance in tomato (Solanum lycopersicum) and Arabidopsis (Arabidopsis thaliana). In response to biotic stress, UBC33 and UBC34 collectively contribute more substantially than UBC32 to plant immunity against Pseudomonas syringae pv. tomato (Pst). Under abiotic stress and ER stress induced by tunicamycin (TM), all three E2s play important roles. Notably, mutation of UBC32 enhances tolerance to TM-induced ER stress, whereas the loss of function in UBC33 or UBC34 suppresses this response. Additionally, UBC32, UBC33, and UBC34 act synergistically in Arabidopsis seed germination under salt stress and abscisic acid (ABA) treatment. While the single mutants atubc32, atubc33, and atubc34 exhibit germination rates comparable to Col-0 under salt stress or ABA treatment, the double mutants atubc32/33, atubc32/34, and atubc33/34 show a significantly greater reduction in germination rate. Interestingly, the atubc32/33/34 triple mutant exhibits a seed germination rate under salt stress and ABA treatment, as well as a level of host immunity to Pst, comparable to that of the atubc33/34 and atubc32/34 double mutants.
CONCLUSIONS: Our findings establish UBC32, UBC33, and UBC34 as key components of the plant ERAD machinery, contributing to plant tolerance to both abiotic and biotic stress. Despite their close phylogenetic relationship, these E2 enzymes exhibit redundant, synergistic, or antagonistic roles depending on the specific stress response pathway, underscoring the complexity of their functional interactions.

Keywords:   Pseudomonas syringae Pv. tomato ; Abiotic stress; Biotic stress; ER stress; Endoplasmic reticulum (ER)-associated protein degradation (ERAD); Ubiquitin-conjugating enzyme (E2)

DOI:  https://doi.org/10.1186/s12870-025-06419-8
Open Biol. 2025 Apr;15(4): 240358

Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.

Alexa Di Pede, Bokang Ko, Abdelrahman AlOkda, Aura A Tamez González, Shusen Zhu, Jeremy M Van Raamsdonk.

  The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that responds to mitochondrial insults by altering gene expression to recover mitochondrial homeostasis. The mitoUPR is mediated by the stress-activated transcription factor ATFS-1 (activating transcription factor associated with stress 1). Constitutive activation of ATFS-1 increases resistance to exogenous stressors but paradoxically decreases lifespan. In this work, we determined the optimal levels of expression of activated ATFS-1 with respect to lifespan and resistance to stress by treating constitutively active atfs-1(et17) worms with different concentrations of RNA interference (RNAi) bacteria targeting atfs-1. We observed the maximum lifespan of atfs-1(et17) worms at full-strength atfs-1 RNAi, which was significantly longer than wild-type lifespan. Under the conditions of maximum lifespan, atfs-1(et17) worms did not show enhanced resistance to stress, suggesting a trade-off between stress resistance and longevity. The maximum resistance to stress in atfs-1(et17) worms occurred on empty vector. Under these conditions, atfs-1(et17) worms are short-lived. This indicates that constitutive activation of ATFS-1 can increase lifespan or enhance resistance to stress but not both, at the same time. Overall, these results demonstrate that constitutively active ATFS-1 can extend lifespan when expressed at low levels and that this lifespan extension is not dependent on the ability of ATFS-1 to enhance resistance to stress.

Keywords:  ATFS-1; Caenorhabditis elegans; ageing; genetics; mitochondrial unfolded protein response; stress resistance

DOI:  https://doi.org/10.1098/rsob.240358