bims-proreb 2026-01-04 papers

bims-proreb

Biomed News

on Proteostasis and redox biology

Issue of 2026–01–04
eleven papers selected by
Shayan Motiei, Universität des Saarlandes

A lysosomal surveillance response promotes healthspan in C. elegans.
Highlights from the Susan Lindquist School on Proteostasis-EMBO|FEBS Lecture Course, 16-19 September, 2025, Espoo, Finland.
Apiin Promotes Healthy Aging in C. elegans Through Nutritional Activation of DAF-16/FOXO, Enhancing Fatty Acid Catabolism and Oxidative Stress Resistance.
Error-prone translation as a driver of proteostasis collapse and neurodegeneration.
Ginseng Oligopeptides Promote Longevity and Enhance Stress Resistance in Caenorhabditis elegans via the DAF-16/FOXO Pathway.
How to measure, analyze, and interpret age-related changes in Caenorhabditis elegans: lessons for mechanistic and evolutionary theories of aging.
Dysregulation of ERAD and Stress Response Proteins by V493F FTO Over-expression: A Proteomic Perspective.
Not Aging but Calorie Restriction Strongly Affects Protein Oxidation in Heart and Brain Mitochondria.
Isolation, Characterization, and Antioxidant Activity of Peptides Derived from Bangia fuscopurpurea.
TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.
Application of the auxin-inducible degron 2 (AID2) system to analyze stage-specific roles of the histone variant H2A.Z during development of C. elegans.

Metabol Open. 2025 Dec;28 100396

A lysosomal surveillance response promotes healthspan in C. elegans.

Liaoyuan Zheng, Junli Liu.

Lysosomes, the cellular recycling hubs, are indispensable for maintaining homeostasis by degrading misfolded proteins, damaged organelles, and foreign pathogens. Their dysfunction is a hallmark of aging and age-related neurodegenerative diseases, where impaired clearance of toxic protein aggregates drives pathogenesis. Nevertheless, the mechanisms by which lysosomal function can be enhanced to mitigate these detrimental processes remain inadequately understood. A recent study conducted by Li et al. describes a newly identified transcriptional program, the Lysosomal Surveillance Response (LySR), that, when activated, significantly extends healthspan and reduces proteotoxicity in C. elegans. This adaptive transcriptional program, governed by the GATA transcription factor, ELT-2, and modulated by the acetyltransferase CBP-1, operates independently of canonical longevity pathways such as the DAF-2 insulin-like signaling. This work not only unveils a previously unrecognized longevity pathway but also charts a new course for developing therapies targeting aging and neurodegeneration.

DOI: https://doi.org/10.1016/j.metop.2025.100396
FEBS Lett. 2026 Jan 03.

Highlights from the Susan Lindquist School on Proteostasis-EMBO|FEBS Lecture Course, 16-19 September, 2025, Espoo, Finland.

Emile van Weert, Chiara Giacomelli, Ioanna Stefani, Maria Li Lopez-Bautista, Antonia-Viktoria Neumeier, Pubali Paul, Anushka Das, Chetan Hari, Ahmet Sadik Gulgec.

  The maintenance of protein homeostasis is a fundamental premise for the survival of all life. The synthesis, folding, localization, and degradation of thousands of proteins must be organized according to various conditions. To ensure such a stable and functional proteome, the proteostasis network evolved. Dedicated to this, the fourth School on Proteostasis, a co-funded EMBO|FEBS Lecture Course in memory of Susan Lindquist, took place in Espoo, Finland on 16-19 September 2025, with 59 early career researchers (PhD students or postdoctoral fellows), 18 leading scientists, and two editors attending and discussing the current state of the field. From basic principles to the latest therapeutic developments, this meeting provided a comprehensive overview of proteostasis. This report summarizes the lecture course and highlights selected presentations.

Keywords:  aging and disease; molecular chaperones; protein degradation; protein quality control; proteostasis; stress responses

DOI:  https://doi.org/10.1002/1873-3468.70261
Int J Mol Sci. 2025 Dec 10. pii: 11888. [Epub ahead of print]26(24):

Apiin Promotes Healthy Aging in C. elegans Through Nutritional Activation of DAF-16/FOXO, Enhancing Fatty Acid Catabolism and Oxidative Stress Resistance.

Yimin Qian, Xuebin Ding, Xinping Guo, Nan Bian, Ying Chen, Shaoyu Han, Wu Song, Lin Wei, Shuang Jiang.

  Apiin, a natural flavonoid sourced from parsley, demonstrates antioxidant properties; however, its specific anti-aging effects have yet to be investigated in Caenorhabditis elegans (C. elegans). This research utilized C. elegans models to examine the anti-aging effects of apiin and the underlying mechanisms. The findings indicated that 100 μg/mL apiin extended the mean lifespan of C. elegans by 26.70%. Furthermore, apiin improved age-related characteristics in C. elegans, such as reducing intestine lipofuscin accumulation and increasing head thrashes and body bends. Additionally, apiin significantly improved stress resistance under thermal, ultraviolet, and oxidative stress conditions. Transcriptomic analysis revealed that apiin induced the differential expression of genes related to fatty acid metabolism, lipid catabolism, and oxidoreductase activity in C. elegans. Metabolomic data further corroborated the modulation of fatty acid metabolic processes by apiin. Biochemical assays, including lipid staining, triglyceride quantification, and measurements of antioxidant enzyme activity, demonstrated a decrease in lipid content and an enhancement in antioxidant capacity in C. elegans treated with apiin. Moreover, apiin promoted the nuclear translocation of DAF-16 and upregulated key longevity-associated genes, including sod-3, hsp-12.6, mtl-1, and ech-9. These results indicate that apiin mitigates aging in C. elegans through mechanisms involving the activation of DAF-16 and the regulation of lipid metabolism and oxidative stress responses. Our findings underscore the potential of apiin as a natural therapeutic agent for aging and associated metabolic disorders.

Keywords:  Caenorhabditis elegans; Daf-16/FOXO pathway; anti-aging; antioxidant; apiin; flavonoids; metabolites

DOI:  https://doi.org/10.3390/ijms262411888
Neural Regen Res. 2025 Dec 30.

Error-prone translation as a driver of proteostasis collapse and neurodegeneration.

Rashid Akbergenov, David P Wolfer, Dennis Gillingham, Dimitri Shcherbakov.

  Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular "tipping point" initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration.

Keywords:  aging; neurological disease; protein aggregation; protein misfolding; protein synthesis; proteostasis; ribosomal mistranslation; translation accuracy

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00795
Antioxidants (Basel). 2025 Nov 21. pii: 1390. [Epub ahead of print]14(12):

Ginseng Oligopeptides Promote Longevity and Enhance Stress Resistance in Caenorhabditis elegans via the DAF-16/FOXO Pathway.

Qian Du, Yiping Zhang, Xiaoyu Guo, Meng Cai, Yong Li, Meihong Xu.

  Background: Ginseng oligopeptides (GOPs), small bioactive peptides with potent antioxidant capacity and high bioavailability, have shown promise in promoting healthy aging; however, their underlying molecular mechanisms remain largely unexplored. Methods: Using the model organism Caenorhabditis elegans (C. elegans), we comprehensively evaluated the anti-aging effects of GOPs on lifespan, locomotion, oxidative stress, and gene expression. Integrated phenotypic assays and transcriptomic analyses were conducted to elucidate GOP-mediated molecular mechanisms. The transgenic strain TJ356 (DAF-16::GFP) and the loss-of-function mutant CF1038 [daf-16(mu86)] were employed to functionally validate the role of the DAF-16/FOXO pathway. Results: GOP supplementation significantly extended median lifespan by approximately 11.5% and improved age-related locomotion decline in C. elegans. Transcriptomic profiling identified 1928 differentially expressed genes (DEGs) enriched in metabolic, antioxidant defense, and longevity-regulating pathways. GOPs upregulated key antioxidant and stress-response genes (gst-4, sod-5, mtl-1) and longevity-related regulators (daf-16, lin-31, Y51B9A.9, and daf-12), while downregulating ins-7, an insulin-like peptide. Moreover, GOPs enhanced cytochrome P450-related detoxification and vitamin-dependent (retinol, ascorbate, and riboflavin) metabolic pathways, establishing a multidimensional antioxidant defense network. Phenotypic validation confirmed that GOPs markedly reduced reactive oxygen species (ROS) levels and lipofuscin accumulation (p < 0.001). Notably, GOPs promoted DAF-16 nuclear translocation in TJ356 worms, whereas the lifespan-extending effects were abolished in CF1038 mutants, highlighting the essential role of DAF-16/FOXO in mediating GOP effects. Conclusions: GOPs delay aging in C. elegans by activating the DAF-16/FOXO signaling cascade and reinforcing antioxidant networks, thereby maintaining redox and metabolic homeostasis. These findings provide novel mechanistic evidence supporting GOPs as promising dietary antioxidants for promoting healthy aging through modulation of conserved redox and longevity pathways.

Keywords:  Caenorhabditis elegans; DAF-16/FOXO pathway; aging; ginseng oligopeptides; longevity; oxidative stress; transcriptomics

DOI:  https://doi.org/10.3390/antiox14121390
Mech Ageing Dev. 2025 Dec 29. pii: S0047-6374(25)00122-8. [Epub ahead of print] 112146

How to measure, analyze, and interpret age-related changes in Caenorhabditis elegans: lessons for mechanistic and evolutionary theories of aging.

Zuzana Kocsisova, Brian M Egan, Andrea Scharf, Xavier Anderson, Franziska Pohl, Aaron Anderson, Kerry Kornfeld.

  Aging is characterized by progressive degenerative changes in tissue organization and function, some of which increase the probability of mortality. Major goals of aging research are to elucidate the series of events that cause degenerative changes, and to identify environmental, pharmacological, and genetic factors that influence these changes; this information might lead to new strategies to extend health span and lifespan. Mechanistic studies of aging depend on accurate and precise descriptions of age-related changes, since these descriptions define the aging phenotype. Here, we review studies that describe age-related changes in C. elegans, including measurements of integrated functions such as behavior and reproduction, microscopic analyses of tissue organization, and biochemical studies of macromolecules. We discuss studies that analyze the relationships between different age-related changes. We consider the results in light of mechanistic and evolutionary theories of aging. Together, these studies provide fundamental insights into aging in C. elegans that may be relevant to aging in other animals.

Keywords:  C. elegans; age-related changes; aging; evolution of aging; longitudinal studies; reproductive aging; somatic aging

DOI:  https://doi.org/10.1016/j.mad.2025.112146
In Vivo. 2026 Jan-Feb;40(1):40(1): 249-263

Dysregulation of ERAD and Stress Response Proteins by V493F FTO Over-expression: A Proteomic Perspective.

Aylin Kanli.

   BACKGROUND/AIM: Demethylase fat mass and obesity-related protein (FTO), which belongs to the AlkB homologous (ABH) family, is associated with various neurological diseases, cancer, and obesity. This protein, which contains many structurally and functionally different regions, contains a COOH-terminal domain whose function, unlike other ABH members, is not fully understood. This study aimed to investigate the effects of the exonic V493F mutation in this region of FTO on the soluble proteome.
MATERIALS AND METHODS: SH-SY5Y cells stably over-expressing wild-type (WT-FTO) or mutant FTO (V493F-FTO) proteins under the control of the Tet promoter were created and used. Comparative proteomic analysis using two-dimensional gel electrophoresis (2DE) identified over 500 protein spots, with 10 showing significant (≥2-fold) differential expression. These proteins were identified by MALDI-TOF/TOF mass spectrometry and validated by western blotting.
RESULTS: WT-FTO over-expression primarily affected proteins related to DNA replication and repair, including PCNA, whereas V493F-FTO over-expression altered the expression of stress response and endoplasmic reticulum-associated degradation (ERAD) pathway proteins, such as HSPA4, ARHGDIA, and VCP. Although the mutation did not alter the nuclear localization or predicted 3D structure of FTO, it distinctly modulated pathways associated with protein homeostasis and cellular stress.
CONCLUSION: FTO participates in the regulation of the cellular stress response and the ubiquitin-dependent ERAD pathway, functions potentially independent of its demethylase activity. Importantly, dysregulation of these pathways has been implicated in cancer initiation, progression, and therapeutic resistance. Therefore, our findings provide new insights into how FTO mutations might influence oncogenic processes, highlighting FTO as a potential biomarker and therapeutic target in cancer biology.

Keywords:  ERAD pathway; FTO protein; V493F mutation; VCP; cancer biology; neuroblastoma cells; proteomics

DOI:  https://doi.org/10.21873/invivo.14188
Aging Cell. 2026 Jan;25(1): e70339

Not Aging but Calorie Restriction Strongly Affects Protein Oxidation in Heart and Brain Mitochondria.

Shipan Fan, Carina Ramallo-Guevara, Monika Frenzel, Shuichi Yanai, Sataro Goto, Michiru D Sugawa, Norbert A Dencher, Ansgar Poetsch.

  Aging is an inevitable consequence for all organisms. According to the mitochondrial free radical theory of aging (MFRTA), reactive oxygen species (ROS), which are predominantly generated in mitochondria, are assumed to play a key role. Calorie restriction (CR) delays aging by improving mitochondrial function; however, the molecular mechanisms underlying the effects of ROS and CR on mitochondria remain poorly understood. Oxidative protein modifications in mitochondrial proteins from the heart and cerebrum of young (6.5 months) and old (27 months) rats were quantified and the effects of short-term and lifelong CR interventions were investigated. Mass spectrometry was leveraged to achieve an unbiased and comprehensive analysis of various types of oxidative postranslational modifications (oxPTMs). Contrary to the MFRTA, aging did not cause significant increases in mitochondrial protein oxidation in the heart and cerebrum. CR markedly diminished the overall level of oxPTMs in the heart, particularly in transmembrane proteins. Similarly, the level of oxidative modification of transmembrane proteins in cerebrum was reduced by CR, whereas it perplexingly increased in mitochondrial proteins. The absolute level of oxidized mitochondrial protein was always higher in the heart than in the cerebrum under all conditions. Carbonylation, a prevalent marker of protein oxidation and aging, increased in the heart with age and was notably reduced by CR. However, this trend was not consistent in cerebrum or for some other types of oxPTMs. Therefore, protein oxidation in the heart and cerebrum exhibits distinct responses to chronological aging and dietary interventions, with the latter exerting a stronger influence.

Keywords:  aging; calorie restriction; mitochondria; oxidative modification

DOI:  https://doi.org/10.1111/acel.70339
Foods. 2025 Dec 09. pii: 4220. [Epub ahead of print]14(24):

Isolation, Characterization, and Antioxidant Activity of Peptides Derived from Bangia fuscopurpurea.

Jiaying Ke, Nan Jia, Yusong Qiu, Chao Zhao.

  Oxidative stress is related to cellular damages and aging. Bioactive peptides have the potential to be a useful functional ingredient, although Bangia fuscopurpurea (red alga), a dense protein source, has not yet been exploited as a source of antioxidant peptide. The aim of the study was to prepare, isolate, and characterize antioxidant peptide of B. fuscopurpurea and assess their protection against oxidative stress in vitro, in HepG2 cells, and in Caenorhabditis elegans. Protein of B. fuscopurpurea was subjected to hydrolysis with papain and purification of the hydrolysate was performed through multi-step chromatography and ultrafiltration. The LC-MS/MS identified peptides, which were synthesized and screened. Two new peptides, YPCW and GYPYK, were discovered and both of them had strong antioxidant properties in vitro, with the ABTS radical scavenging IC50 of 2.52 ± 0.37 µg/mL and ORAC of 5187 ± 78 µmol TE/g. Both peptides in H2O2-induced HepG2 cells significantly decreased the intracellular ROS and MDA and inhibited the activity of antioxidant enzymes (SOD, CAT, and GSH-Px). Moreover, YPCW and GYPYK increased the survival of C. elegans during oxidative stress and the similar response, altering antioxidant enzyme activities in vivo and MDA levels. These findings indicate that peptides obtained through B. fuscopurpurea can be useful as antioxidant agents, and they can be considered as a possible new active ingredient of functional foods or pharmaceuticals to counteract oxidative stress.

Keywords:  Bangia fuscopurpurea; Caenorhabditis elegans; HepG2; antioxidant peptide; oxidative stress

DOI:  https://doi.org/10.3390/foods14244220
Sci Adv. 2026 Jan 02. 12(1): eaea9302

TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.

Maria Iavazzo, Laura Cinque, Sophie Levantovsky, Castrese Morrone, Jlenia Monfregola, Andrea Raimondi, Elena Polishchuk, Rossella De Cegli, Diego Carrella, Edoardo Nusco, Luigi Ferrante, Francesca Sacco, Lisa B Frankel, Christian Behrends, Carmine Settembre.

(Macro)autophagy is a conserved cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among various physiological stimuli, nutrient starvation is the most potent inducer of autophagy. In response to starvation, transcription factor EB (TFEB) is activated and up-regulates a broad set of autophagy-related genes. However, the mechanisms by which TFEB promotes autophagosome biogenesis remain incompletely understood. Here, we demonstrate that TFEB-mediated transcriptional induction of sequestosome 1 (SQSTM1; p62) triggers the formation of SQSTM1-positive bodies that recruit essential autophagy factors, thereby initiating autophagosome biogenesis. Genetic disruption of TFEB-dependent SQSTM1 regulation markedly impairs starvation-induced autophagy, underscoring the critical role of the TFEB-SQSTM1 axis in the autophagic response to nutrient stress. Furthermore, we show that these SQSTM1 bodies contain ubiquitinated ribosomal proteins and that TFEB promotes ribosomal protein ubiquitination by inducing the E3 ubiquitin ligase ZNF598. Collectively, our findings uncover a transcriptionally coordinated mechanism that regulates both autophagosome biogenesis and substrate ubiquitination, facilitating efficient cargo clearance during starvation-induced autophagy.

DOI: https://doi.org/10.1126/sciadv.aea9302
Biosci Biotechnol Biochem. 2025 Dec 31. pii: zbaf200. [Epub ahead of print]

Application of the auxin-inducible degron 2 (AID2) system to analyze stage-specific roles of the histone variant H2A.Z during development of C. elegans.

Natsumi Horii, Saho Kitagawa, Yukako Oma, Nami Haruta, Asako Sugimoto, Masato Kanemaki, Masahiko Harata.

  Multiple roles of the evolutionarily conserved histone variant H2A.Z in development have been proposed. However, conventional H2A.Z knockouts cause embryonic lethality. Here, we developed a transient depletion system for H2A.Z in Caenorhabditis elegans using an auxin-inducible degron and demonstrated its contribution to germline differentiation at early developmental stages. This system can be applied to investigate temporal protein functions during development.

Keywords:   C. elegans ; H2A.Z; auxin-induced degron; germline development

DOI:  https://doi.org/10.1093/bbb/zbaf200