Hundreds of mitochondrial proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphiphilic helices, presequences lack a consensus motif and thus likely promote protein import into mitochondria with variable efficiencies. Indeed, the concept of presequence strength underlies biological models such as stress sensing, yet a quantitative analysis of what dictates strong versus weak presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the MitoLuc protein import assay to define multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPRmt), impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those associated with stress signaling promote highly variable import efficiency in vitro, suggesting presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust in vitro import can fully rescue defects in respiratory growth in complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as weak or strong requires more nuanced characterization than typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.

Targeting ER stress in adrenocortical carcinoma: Celastrol as a novel therapeutic candidate.

Hydrogen sulfide (H2S), known as a metabolic modulator, is a gaseous signaling molecule with functions similar to those of nitric oxide and carbon monoxide, all of which possess vasodilatory, antioxidant, and other properties. In the central nervous system, H2S is a signaling molecule that is crucial for neuroprotection and the control of neurological processes. The paraventricular nucleus (PVN) of the hypothalamus is an important central nucleus that regulates and integrates cardiovascular and peripheral sympathetic activity. This study aimed to investigate whether intra-PVN injection of the endogenous H2S synthase CBS activator S-adenosylmethionine (SAMe) or the endogenous H2S synthase CBS inhibitor hydroxylamine (HA) modulates H2S expression in the PVN, whether microglia in the PVN are targeted by H2S, and whether PVN H2S further induces alterations in blood pressure(BP) by affecting endoplasmic reticulum(ER) stress in the PVN of spontaneously hypertensive rats (SHR). Healthy male Wistar-Kyoto (WKY) rats and SHR were fed a normal diet for 8weeks, followed by intra-PVN injections of SAMe, HA, or vehicle for 4weeks. Plasma norepinephrine levels and mean arterial pressure were elevated in the SHR group. The expression of factors related to ER stress, such as p-PERK, GRP78, and p-IRE1α, was also elevated. Levels of these parameters were lower in the SHR+SAMe group, whereas the SHR + HA group presented with higher levels of these indicators. These findings suggest that endogenous H2S attenuates sympathetic activity and hypertensive responses in the PVN, in part by modulating ER stress.

FGF2-targeted Timosaponin AIII provokes ER stress and dampens PI3KAKT signaling pathway in breast cancer.

The C-domain of the cerebral dopamine neurotrophic factor (CDNF) is responsible for its cardioprotective activity by binding to the KDEL receptor relocated to the plasma membrane under endoplasmic reticulum stress conditions.

Nitrogen Species Modulate Macrophage ER Stress to Preserve Alveolar Bone: A Translational Adjunct for Periodontal Care.

Drug-induced liver injury (DILI) from acetaminophen (APAP) overdose involves ER stress, oxidative damage, apoptosis, and inflammation. This study assesses Terminalia arjuna bark extract (TAE) against APAP-induced toxicity in rats, comparing its efficacy with N-acetylcysteine (NAC) through key signaling and inflammatory markers. Twenty-four Wistar rats were equally divided into four groups: Control Negative (CN, no treatment), Control Positive (CP, acetaminophen 350 mg/kg), N-acetylcysteine (NAC, 150 mg/kg), and Terminalia arjuna bark extract (TAE, ethanolic, 80 mg/kg). Over 14 days, liver injury was induced in the CP group via acetaminophen, while the NAC and TAE groups received their respective treatments. Animals were decapitated on day 15, and biological samples were collected for analysis. Biochemical assessments included liver function markers (ALT, AST) and oxidative stress parameters (SOD, TAC, TBARS, TOS). Gene expression studies were performed for oxidative stress regulators (Keap1, Nrf2) and ER stress signaling molecules (ERK, JNK, PPAR-α, AKT). Histopathological examination evaluated liver architecture and cellular integrity. Acetaminophen induced significant hepatotoxicity, as reflected by elevated liver enzymes, increased oxidative stress, altered gene expression, and disrupted liver histology. APAP toxicity resulted in elevated oxidative stress, apoptosis, inflammation, and ER stress, leading to significant hepatic damage (p < 0.0001 vs CN). NAC and TAE treatments mitigated these effects, with TAE demonstrating superior improvement in oxidative stress markers (p < 0.0001 vs CP). Gene expression analysis revealed a protective shift in the Keap1-Nrf2 pathways in the treated groups. Histopathology confirmed reduced necrosis and preserved hepatic architecture in the NAC and TAE groups. T. arjuna exhibits potent hepatoprotective effects, comparable to NAC, through modulation of oxidative stress, apoptosis, and ER stress pathways. Further studies are needed to explore its clinical applicability in acute liver injury management.

Uterine fibroids involve abnormal cell proliferation and fibrosis, with epithelial-mesenchymal transition (EMT) playing a key role. Mitochondrial-endoplasmic reticulum stress and related signaling pathways are implicated in this process, but the potential of natural extracts for modulation remains underexplored. This study aimed to investigate whether Atractylodes macrocephala extract can reverse EMT progression in uterine fibroids by regulating mitochondrial-endoplasmic reticulum stress via relevant signaling pathways. A mouse model of uterine fibroids was established and divided into normal, model, and Atractylodes macrocephala extract groups. Measurements included uterine weight, organ coefficient, cell proliferation, and apoptosis rate. Caspase-4 activity analysis, Western blotting, and immunofluorescence microscopy were used to assess protein and gene expression related to EMT, apoptosis, and signaling pathways. The uterine fibroid model was successfully established. Treatment with Atractylodes macrocephala extract significantly inhibited uterine fibroid cell proliferation, promoted apoptosis, and reduced fibrosis. Mechanistically, the extract ameliorated EMT by effectively suppressing PI3K/Akt pathway activity. It concurrently exacerbated endoplasmic reticulum stress (indicated by increased Caspase-4 activity) to promote apoptosis while enhancing lysosome generation. Atractylodes macrocephala extract inhibits proliferation, promotes apoptosis, and reduces fibrosis in uterine fibroids by suppressing the PI3K/Akt pathway and enhancing endoplasmic reticulum stress. These findings provide a novel strategic basis for developing natural targeted therapies against uterine fibroids.

Insulin resistance: The central node of convergence between unfolded protein response, diabetes, and cancer.

Unraveling stress-adaptation pathways in cancer: Functional dissection through CRISPR-based genetic screens.

Bisphenol A induces IRE1-dominant endoplasmic reticulum stress, apoptosis, and functional impairment in BeWo trophoblast cells.

Streptococcus vaginalis affects cellular dynamics of cervical cancer cells via oxidative stress-induced activation of endoplasmic reticulum unfolded protein response.

Amyloid oligomers are increasingly recognized as the major toxic contributors across protein-misfolding disorders. In this review, we cover mechanistic evidence showing how these transient and structurally heterogeneous oligomers disrupt cellular homeostasis by: (i) permeabilizing lipid membranes and forming ion-conducting pores; (ii) triggering endoplasmic reticulum (ER) stress and unfolded protein response (UPR), thereby compromising proteostasis via dysfunction of the ubiquitin-proteasome system (UPS) and autophagy; (iii) impairing mitochondrial function and disrupting redox balance; (iv) interfering with endosomal-lysosomal as well as axonal and synaptic trafficking; and (v) activating stress-kinase signaling and apoptotic pathways. In relation to therapeutic intervention, we review secretase-targeting strategies, conformation-selective antibodies, and their mixed clinical outcomes. An in-depth understanding of the toxic action of pathogenic oligomeric species will be critical for translating these mechanistic insights into effective therapies that comprehensively target oligomer toxicity.

TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury.

Targeting the Nrf2/HO-1 aixs: A therapeutic strategy against regulated cell death in Alzheimer's disease.

A near-infrared viscosity probe for dynamic imaging of multilevel drug-induced liver injury.

Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects, but its mechanism of action in PD remains unclear. This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. An in vitro neuroinflammation model was established using LPS-treated astrocytes. In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-α, IL-1β), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS.

Mechanistic insights into stem cell aging: Pathways and processes.

Sinapic acid attenuates vancomycin-induced hepatotoxicity in rats via modulation of ER stress (CHOP, IRE1, ATF-6, PERK), apoptotic pathways (caspase-3, Bax/Bcl-2, Apaf-1, cytochrome-c), and antioxidant defenses.

Mechanisms of Traditional Chinese Medicine in regulating Nrf2-related signaling pathways for the treatment of Oligoasthenozoospermia: A review.