bims-proreb 2025-11-09 papers

bims-proreb

Biomed News

on Proteostasis and redox biology

Issue of 2025–11–09
eleven papers selected by
Shayan Motiei, Universität des Saarlandes

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.
How Pathogens Maintain Proteostasis During Infection.
Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.
Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.
Low-dose ionizing radiation promotes lifespan extension and stress resistance of C. elegans via DAF-16/SKN-1 mediated adaptive response.
Germline regulation of the intestinal mitochondrial unfolded protein response.
Defining the necessity of the lipoic acid synthase lias-1 in Caenorhabditis elegans.
Nonlinear integration of sensory inputs and behavioral state by a single neuron in C. elegans.
Presenilin mutations disrupt iron homeostasis to promote ferroptosis mediated neurodegeneration in Caenorhabditis elegans.
Hsp90 co-chaperone FKBP4 facilitates CCT8 folding and connects Hsp90 to chaperonin-dependent proteostasis.
Dark tea extract extends Caenorhabditis elegans lifespan by enhancing antioxidant and ferroptosis resistance.

Geroscience. 2025 Nov 04.

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.

Juri Kim, Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.

  Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores the function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, a decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt promote longevity. These and other studies have started to question whether UPRmt is directly correlated with longevity. Here, we attempt to address this controversy by unraveling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce mitochondrial stress by performing RNA sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPRmt and longevity. Altogether, this study will provide mechanistic insights on mitohormesis and how it correlates with the lifespan of C. elegans.

Keywords:  Aging; Caenorhabditis elegans; Mitohormesis; UPRmt

DOI:  https://doi.org/10.1007/s11357-025-01912-2
Mol Microbiol. 2025 Nov 04.

How Pathogens Maintain Proteostasis During Infection.

Carissa Chan, Eduardo A Groisman.

  Molecular chaperones play a critical role in proteostasis by aiding the folding of newly synthesized proteins and the refolding of misfolded proteins. Cells must match the protein synthesis rate to the protein folding capacity to avoid the accumulation of unfolded proteins that can form toxic aggregates. The Hsp70 chaperone DnaK binds to ribosomes and decreases protein synthesis in the bacterial pathogen Salmonella enterica serovar Typhimurium when facing cytoplasmic Mg2+ starvation, an infection-relevant stress that disrupts proteostasis. DnaK decreases protein synthesis independently of J-domain cochaperones and nucleotide exchange factor GrpE even though J-domain cochaperones and GrpE are required for DnaK's canonical role in protein folding and refolding. DnaK's activity contrasts with that exhibited by the bacteria-specific chaperone trigger factor, which associates with ribosomes and carries out cotranslational protein folding in Mg2+-abundant conditions. Under infection-relevant conditions, the master regulator of S. typhimurium virulence and Mg2+ homeostasis PhoP promotes the expression of DnaK, but not of J-domain cochaperones, GrpE, or trigger factor, suggesting that the differential expression of chaperones and cochaperones furthers S. typhimurium pathogenesis. Hsp70 chaperones also associate with ribosomes in eukaryotic cells but instead promote protein synthesis, the opposite effect that DnaK binding to ribosomes has in bacteria. Thus, Hsp70 chaperone activity differs across growth conditions and among organisms.

Keywords:  DnaK; Hsp70; J‐domain cochaperone; PhoP; RpoH; magnesium; protein folding; protein synthesis; trigger factor

DOI:  https://doi.org/10.1111/mmi.70034
Pharmacol Rev. 2025 Oct 14. pii: S0031-6997(25)07504-0. [Epub ahead of print]77(6): 100096

Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.

Michael Karin, Ju Youn Kim.

The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.

DOI: https://doi.org/10.1016/j.pharmr.2025.100096
Front Mol Neurosci. 2025 ;18 1639114

Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.

Zhanguo Su, Lijuan Xiang.

  The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.

Keywords:  ER stress; exercise; muscle function; neurodegenerative diseases; unfolded protein response

DOI:  https://doi.org/10.3389/fnmol.2025.1639114
Ecotoxicol Environ Saf. 2025 Nov 03. pii: S0147-6513(25)01678-1. [Epub ahead of print]306 119333

Low-dose ionizing radiation promotes lifespan extension and stress resistance of C. elegans via DAF-16/SKN-1 mediated adaptive response.

Ge Zhang, Lei Zhao, Zejun Li, Yuhan Dong, Zaishuang Ju, Yeqing Sun.

  Exposure to ionizing radiation (IR) has raised significant concern regarding potential health risks, particularly the frailty-like syndromes. Paradoxically, emerging evidence suggests that low-dose IR exposure may exert opposite effects. In this study, we show that exposure to 0.5 and 2.0 Gy X-rays extends lifespan in C. elegans. We demonstrate that elevated levels of persistent reactive oxygen species (ROS) and mitochondrial ROS induced by low-dose IR act as key drivers in activating the transcription factors (TFs) DAF-16 and SKN-1 in C. elegans. Additionally, we elucidate that under low-dose IR exposure, DAF-16 regulates the expression of skn-1, while SKN-1 binds to the promoters of antioxidant genes through a conserved motif, thereby initiating adaptive responses that maintain redox homeostasis, enhance stress resistance, and ultimately promote lifespan extension. This work identifies a critical regulatory network that drives lifespan extension and stress resistance in C. elegans, and provides candidate targets and mechanistic insights for preventive interventions aimed at mitigating IR-induced aging and lifespan shortening.

Keywords:  Antioxidant pathway; Caenorhabditis elegans; Ionizing radiation; Lifespan extension; Mitochondrial stress; Stress resistance

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119333
Geroscience. 2025 Nov 07.

Germline regulation of the intestinal mitochondrial unfolded protein response.

Anna C Foulger, Nathaniel A Jordan, Alyssa Castle, Dipa Bhaumik, Julie K Andersen, Gordon J Lithgow, Suzanne Angeli.

  The disposable soma theory posits that there is a trade-off between reproduction and somatic maintenance. In support of this theory, we previously identified that pharmacological inhibition of the germline has widespread protective cell non-autonomous effects on cellular protein homeostasis in the model organism Caenorhabditis elegans. However, the cell non-autonomous effects of the germline on mitochondrial protein homeostasis are not well defined. Here, we use pharmacological or genetic inhibition of the germline to determine its effects on intestinal mitochondrial protein homeostasis as measured by the mitochondrial unfolded protein response (UPRmt). We find that pharmacological inhibition of germline proliferation by 5-fluoro-2-deoxyuridine (FUdR), a DNA synthesis inhibitor, potently inhibits activation of the intestinal UPRmt as well as reverses lifespan effects induced by mitochondrial dysfunction. We find similar results with the genetic mutant (glp-1), which lacks germline proliferation. To further identify the reproductive processes required to regulate the intestinal UPRmt, we examined the genetic mutant fem-1, which contains an intact gonad with oocytes but lacks sperm. Like glp-1 mutants, fem-1 mutants do not activate the intestinal UPRmt due to mitochondrial dysfunction caused by loss of OXPHOS subunits. Restoring reproduction in fem-1 mutants by mating them with wild type males is sufficient to reactivate the intestinal UPRmt. Furthermore, loss of the FOXO transcription factor daf-16 is sufficient to reactivate the intestinal UPRmt in fem-1 mutants and partially in glp-1 mutants. These findings suggest that FOXO/daf-16 acts to limit UPRmt activation in the intestine. These findings also suggest that late-stage reproductive signals that include the maturation of oocytes and fertilization may play a critical role in cell non-autonomous intestinal UPRmt activation.

Keywords:   Caenorhabditis elegans ; Cell non-autonomous; Fertilization; Germline; Intestines; Mitochondrial unfolded protein response; Reproduction

DOI:  https://doi.org/10.1007/s11357-025-01890-5
MicroPubl Biol. 2025 ;2025

Defining the necessity of the lipoic acid synthase lias-1 in Caenorhabditis elegans.

Linnea B Parker, Philippa Murray, Peter A Kropp.

Lipoic acid is an essential cofactor for multiple enzymes involved in aerobic respiration, and disruption to any of the pathways contributing to lipoic acid synthesis result in severe respiratory dysfunction. Despite the importance of lipoic acid, few studies have directly investigated the necessity of the lipoic acid synthase itself in eukaryotes. We have used Caenorhabditis elegans to address this gap and created CRISPR knockouts of lias-1 , the first lias-1 knockouts reported in C. elegans . These mutants show developmental arrest, sterility, and shortened lifespan which cannot be rescued by supplementing with exogenous lipoic acid suggesting a necessity for de novo lipoic acid synthesis in C. elegans .

DOI: https://doi.org/10.17912/micropub.biology.001804
Curr Biol. 2025 Oct 31. pii: S0960-9822(25)01314-4. [Epub ahead of print]

Nonlinear integration of sensory inputs and behavioral state by a single neuron in C. elegans.

Amanda Ray, Andrew Gordus.

  Context is important for sensory integration; however, explicitly modeling this property as a function of precise presynaptic inputs is not trivial. In Caenorhabditis elegans, the paired interneurons AIBL and AIBR (AIB) integrate both sensory and motor information and strongly drive reversal behavior. Through a series of experiments to monitor reversal behavior and manipulate sensory input onto AIB, we find that while AIB activity is primarily a convolution of behavioral state, its sensory responses are not integrated independently. Instead, the gain in sensory input increases during the transition to the reversal state. Sensory information therefore reinforces the decision to reverse. Context-dependent behavioral responses to sensory input are well-documented. Here, we show this property can be localized to single neurons in the nematode nervous system. This integration property likely plays an important role in context-dependent decision-making, as well as the highly variable dynamics of the C. elegans nervous system.

Keywords:  C. elegans; behavior; integration; interneuron; motor; nematode; nonlinear; sensory

DOI:  https://doi.org/10.1016/j.cub.2025.10.006
Redox Biol. 2025 Oct 30. pii: S2213-2317(25)00423-9. [Epub ahead of print]88 103910

Presenilin mutations disrupt iron homeostasis to promote ferroptosis mediated neurodegeneration in Caenorhabditis elegans.

Kerry C Ryan, Jocelyn T Laboy, Rabia Ashraf, Zahra Ashkavand, Isabel Jayasinghe, Kenneth R Norman.

Iron is a vital trace element involved in numerous physiological processes, but it becomes toxic when present in excess. Disruption of iron balance in the brain has been linked to the development of neurodegenerative diseases such as Alzheimer's disease (AD), though the underlying mechanisms remain poorly understood. Familial forms of AD are primarily caused by mutations in presenilin, which are known to disturb cellular calcium homeostasis. However, the role of iron in presenilin-related neurodegeneration has not been fully explored. Using C. elegans as a model organism, we investigated the function of SEL-12, the worm ortholog of presenilin, and found that loss of SEL-12 leads to elevated iron levels and increased expression of FTN-2/ferritin, an iron-sequestering protein. Notably, reducing mitochondrial calcium in sel-12 mutants prevented this iron accumulation, indicating that elevated mitochondrial calcium drives increased cellular iron levels. This iron overload depends on mitochondrial superoxide production, which occurs alongside heightened mitochondrial calcium, suggesting that oxidative stress contributes to iron dysregulation. The resulting iron imbalance causes mitochondrial and lysosomal dysfunction, ultimately impairing neuronal and behavioral function. Supporting the involvement of iron, sel-12 mutants exhibit elevated lipid peroxidation, and inhibition of ferroptosis restores neuronal function. Together, these findings reveal a novel role for presenilin in regulating iron homeostasis and identify a mechanism linking calcium signaling disruption to iron dyshomeostasis and neurodegeneration.

DOI: https://doi.org/10.1016/j.redox.2025.103910
J Biol Chem. 2025 Nov 05. pii: S0021-9258(25)02766-8. [Epub ahead of print] 110914

Hsp90 co-chaperone FKBP4 facilitates CCT8 folding and connects Hsp90 to chaperonin-dependent proteostasis.

Yun-Yu Huang, Ya-Lan Chang, Yun Chen, Wei-Yu Chiang, Ai-Tao Chiang, Pang-Hung Hsu, Shu-Chun Teng.

  Hsp70, Hsp90, and chaperonin complexes are three essential molecular chaperones facilitating protein folding within eukaryotic cells. However, the important interplay among these systems is incompletely understood. FKBP4 is a co-chaperone of Hsp90 and exhibits increased expression in multiple types of cancers. In this study, we employed two proximity-dependent biotin identification (BioID) systems to explore potential clients of the FKBP4-Hsp90 complex. Analysis of BioID mass spectrometry data revealed that the top category of the FKBP4-associated protein is cadherin-binding proteins, and one of the cadherin-binding proteins is a subunit of the chaperonin containing TCP-1 complex, CCT8. Furthermore, knockdown of FKBP4 led to the aggregation of CCT8 and compromised the stability of CCT8 clients, CDK2 and α-tubulin, indicating the dependency of the FKBP4-Hsp90 complex for CCT8 folding. These findings suggest that CCT8 is a client of the FKBP4-Hsp90 complex, implying a functional crosstalk between two of the three protein folding systems in eukaryotic cells.

Keywords:  CCT8; FKBP4; Hsp90; chaperonin; client; co-chaperone

DOI:  https://doi.org/10.1016/j.jbc.2025.110914
Food Res Int. 2025 Dec;pii: S0963-9969(25)01841-1. [Epub ahead of print]221(Pt 4): 117503

Dark tea extract extends Caenorhabditis elegans lifespan by enhancing antioxidant and ferroptosis resistance.

Dongni Wu, Mengjiao Hao, Lingli Sun, Xingfei Lai, Ruohong Chen, Zhenbiao Zhang, Qiuhua Li, Suwan Zhang, Xi Zheng, Shili Sun, Dongli Li.

   BACKGROUND: Numerous epidemiological studies have found that tea consumption has an anti-aging and preventive effect on age-related diseases. The question of which tea possesses the most potent anti-aging properties and the underlying mechanisms of these effects remains largely obscure.
PURPOSE: To explore which type of tea has the strongest anti-aging activity and its mechanism of action.
METHODS: The Caenorhabditis elegans (C. elegans) longevity and stress tests were used to evaluate the anti-aging activities of six types of tea. Additionally, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was employed to compare the differences in anti-aging-related chemical components among these teas. These analyses were conducted to identify the tea with the strongest anti-aging activity and to further explore its underlying molecular mechanisms.
RESULTS: All the extracts of tea (200 μg/mL) prolonged life and enhanced stress resistance. Surprisingly, dark tea (DT) had significant anti-aging efficacy. Furthermore, this study found that anti-aging mechanisms of DT include (a) DT modulated the IGF-1 signaling pathway (IIS), SKN-1 and HSF-1 stress resistance pathway, and the AMPK/SIRT1/FOXO signaling pathway. (b) DT upregulated skn-1 and ftn-1 expression, decreased Fe2+ levels, and inhibited ferroptosis. (c) DT preserved the integrity and functionality of mitochondria.
CONCLUSION: This study demonstrated that DT significantly extended lifespan by enhancing antioxidant capacity, maintaining mitochondrial function and suppressing ferroptosis in C. elegans. These anti-aging effects mediated by multiple mechanisms. Furthermore, the anti-aging properties of DT are partly attributed to its high flavonoid levels.

Keywords:  Anti-aging; Antioxidant; C. elegans; Dark tea; Ferroptosis

DOI:  https://doi.org/10.1016/j.foodres.2025.117503