bims-proreb 2025-11-23 papers

bims-proreb

Biomed News

on Proteostasis and redox biology

Issue of 2025–11–23
eight papers selected by
Shayan Motiei, Universität des Saarlandes

Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.
Phenotypic and metabonomics studies of FMOs in C. elegans and their roles in lifespan extension.
Multi-target synergistic anti-aging: QG extends Caenorhabditis elegans lifespan through DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming.
Antioxidant and anti-aging effects of quercetin 3-O-rhamnoside isolated from Houttuynia cordata Thunb extract on Caenorhabditis elegans.
Neuroprotective Parkinson's Disease Therapeutic: Transition Metal Dichalcogenide Nanoflower Treatments Alleviate Pathological Cell Stress.
DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.
RiboTRAP-seq identifies spatially distinct functions for the anterior and posterior intestine in immune and metabolic regulation in C. elegans.
Role of p62 nuclear condensates in regulating ubiquitin-mediated proteasomal degradation.

bioRxiv. 2025 Oct 04. pii: 2025.02.11.637611. [Epub ahead of print]

Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.

Priyanka Das, Ravi, Jogender Singh.

Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for lifespan modulation, we conduct a genome-wide bacterial mutant screen and identify 26 Escherichia coli mutants that enhance host lifespan. Transcriptomic and biochemical analyses reveal that these mutant diets induce oxidative stress and activate the mitochondrial unfolded protein response (UPRmt). Antioxidant supplementation abolishes lifespan extension, confirming that oxidative stress drives these effects. The extension of lifespan requires the oxidative stress response regulators SKN-1, SEK-1, and HLH-30. Mechanistically, these effects are linked to reduced iron availability, as iron supplementation restores FAT-7 expression, suppresses UPRmt activation, and abolishes lifespan extension. Iron chelation mimics the pro-longevity effects of the mutant diets, highlighting dietary iron as a key modulator of aging. Our findings reveal a bacterial-host metabolic axis that links oxidative stress, iron homeostasis, and longevity in C. elegans .

DOI: https://doi.org/10.1101/2025.02.11.637611
Metabolomics. 2025 Nov 15. 21(6): 170

Phenotypic and metabonomics studies of FMOs in C. elegans and their roles in lifespan extension.

Mohamed Said, Rafael Freire, Filipe Cabreiro, Jose Ivan Serrano-Contreras, Elinor P Thompson, Jeremy R Everett.

   INTRODUCTION: Flavin-Containing Monooxygenases (FMO) are widely conserved, xenobiotic-detoxifying enzymes whose additional endogenous functions have been revealed in recent studies. Those roles include the regulation of longevity in the model nematode Caenorhabditis elegans.
OBJECTIVES: The purpose of this study was to compare aspects of the phenotypes of C. elegans worms with mutations in all fmo genes, particularly focusing on the metabolome and its relationship with lifespan-extension and the worm life cycle. This is the first systematic study of the effect of fmo genetic variation on C. elegans metabolic profiles that we are aware of.
METHODS: NMR Spectroscopic analysis of the extracts of metabolites from C. elegans worms of different ages and fmo genotypes was used to compare metabolite profiles of C. elegans worms and determine how these changed with genotype and ageing.
RESULTS: Loss of both fmo-4 and fmo-3 and over-expression of fmo-2, resulted in increased levels of tryptophan in the metabolome, which correlated with an extended lifespan in these mutants. Loss of fmo-4 also led to decreased embryo hatching, along with increased sensitivity to bleach during sterilisation protocols. In contrast, in the extended lifespan fmo-1 knockout worm, the metabolome did not reveal any significant metabolite changes and therefore lifespan effects may occur through another mechanism, or hidden metabolic changes.
CONCLUSION: Genetic interventions coupled with metabolome profiling in C. elegans can provide insights into biological mechanisms in ageing that might lead to strategies for healthy lifespan extension in human old age.

Keywords:   C. elegans ; FMO Genotypes; Lifespan; Metabolomics; Metabonomics; NMR Spectroscopy

DOI:  https://doi.org/10.1007/s11306-025-02367-4
Biogerontology. 2025 Nov 18. 27(1): 6

Multi-target synergistic anti-aging: QG extends Caenorhabditis elegans lifespan through DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming.

Jiahui Wang, Shuqi Li, Zichen Lei, Yantao Xing, Jieshu Li, Jie Guo, Boshi Duan, Yonggang Liu.

  Aging not only significantly reduces the quality of life for the elderly but also poses multifaceted challenges to society. Its progression involves the synergistic interaction of multidimensional, multipathway molecular mechanisms, including mitochondrial dysfunction, oxidative stress accumulation, chronic inflammation, and genomic damage. Quercetagetin (QG), as a natural flavanol monomer, exhibits significant potential in anti-aging due to its simultaneous targeting of key aging pathways such as oxidative stress and chronic inflammation. We first evaluated QG's safety profile, finding that 0.02 mg/ml QG did not adversely affect motility, feeding, growth, and reproductive capacity in Caenorhabditis elegans (C. elegans). At this concentration, in vivo experiments using wild-type C. elegans confirmed QG's ability to extend lifespan and enhance oxidative stress resistance. The antioxidant and anti-aging effects of QG were further validated using the daf-16 mutant C. elegans DR26. Subsequently, observation of QG's impact on C. elegans mitochondrial morphology revealed significant reductions in area/perimeter and mitochondria coverage ratio following treatment. This indicates that QG treatment shifts the mitochondrial network from fusion toward fission and reduces overall mitochondrial content. QG can also improve age-related dopaminergic, 5-hydroxytryptaminergic and cholinergic neuron degeneration. Mass spectrometry metabolome analysis revealed that QG significantly affected citrate cycle and glycerophospholipid metabolism. Collectively, QG extends C. elegans lifespan by regulating redox homeostasis, DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming. This multi-target regulatory capacity positions QG as an ideal candidate molecule for anti-aging drug development.

Keywords:   C. elegans ; Anti-aging; DAF-16/FOXO pathways; Metabolic reprogramming; Mitochondrial homeostasis; Quercetagetin

DOI:  https://doi.org/10.1007/s10522-025-10347-3
Free Radic Biol Med. 2025 Nov 14. pii: S0891-5849(25)01371-1. [Epub ahead of print]243 143-156

Antioxidant and anti-aging effects of quercetin 3-O-rhamnoside isolated from Houttuynia cordata Thunb extract on Caenorhabditis elegans.

Hyeon Ji Kim, Suk Heung Oh, Jun Hyeong Kim.

  Humans inevitably generate reactive oxygen species (ROS) during respiration, leading to oxidative stress, which antioxidants counteract. However, aging and lifestyle factors increase ROS levels, contributing to disease. This study evaluated the antioxidant and anti-aging effects of Houttuynia cordata extract and fractions using Caenorhabditis elegans. The most active ethyl acetate (EA) fraction was isolated via open column chromatography and identified as quercetin 3-O-rhamnoside (quercitrin) through NMR and LC-MS/MS analysis. Antioxidant enzyme activities (SOD, catalase, SOD-3) and intracellular ROS inhibition were assessed, alongside stress resistance under oxidative and thermal conditions. Additionally, quercitrin's effects on aging were examined by measuring SIR2.1 and DAF-2 expression in the insulin signaling pathway (IIS) and analyzing its concentration-dependent regulation of DAF-16 using GFP transgenic worms. Quercitrin modulated aging related proteins, enhanced antioxidant enzyme activity, inhibited ROS accumulation, extended lifespan, and improved resistance to thermal stress. These findings highlight quercitrin's strong antioxidant and anti-aging properties.

Keywords:  Anti-aging; Antioxidant; Caenorhabditis elegans; Houttuynia cordata Thunb; Quercetin 3-O-rhamnoside (Quercitrin); ROS; Western blot

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.026
bioRxiv. 2025 Oct 01. pii: 2025.09.29.679305. [Epub ahead of print]

Neuroprotective Parkinson's Disease Therapeutic: Transition Metal Dichalcogenide Nanoflower Treatments Alleviate Pathological Cell Stress.

Charles L Mitchell, Mikhail Matveyenka, Harris C Brown, Jessica Aldape, Payton Moore, Kha-Tran Nguyen, John C Walker, Bryce Pearson, Joshua Skrehot, Dmitry Kurouski.

Parkinson's disease (PD) is triggered by irreversible degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus. Although the underlying molecular etiology of these pathological processes remains unclear, progressive aggregation of alpha-synuclein (α-syn) and mitochondrial dysfunction are two expected mechanisms implicated in neuronal degeneration. Accumulating evidence indicates that transition metal dichalcogenide (TMD) nanoflowers (NFs), a novel class of nanomaterials, can restore mitochondrial health by the activation of mitochondrial biogenesis. However, therapeutic potential of TMD NFs in PD remains unclear. The current study investigates the neuroprotective properties of molybdenum disulfide (MoS 2 ) and molybdenum diselenide (MoSe 2 ) nanoflowers (NFs) in neurons and astrocytes exposed to α-syn aggregates. It was found that MoS 2 and MoSe 2 suppressed α-syn-induced unfolded protein response (UPR) in the endoplasmic reticulum, and upregulated autophagy and exocytosis of α-syn fibrils. TMD NFs also reversed α-syn-induced damage of cell mitochondria, simultaneously stimulating mitochondrial biogenesis. As a result, a drastic decrease in ROS levels in both neurons and astrocytes was observed. These results show that MoS 2 or MoSe 2 NFs could fully rescue neurons and astrocytes from the cytotoxic effects of α-syn fibrils. Neuroprotective properties of these novel nanomaterials were further explored in Caenorhabditis elegans that overexpress α-syn. Nematodes that received NFs experienced a drastic reduction in the amount of aggregated α-syn which resulted in a significant increase in C. elegans lifespan. These findings indicated that MoS 2 or MoSe 2 NFs could be used as novel therapeutic to decelerate the progression of PD.

DOI: https://doi.org/10.1101/2025.09.29.679305
bioRxiv. 2025 Oct 02. pii: 2025.10.02.680111. [Epub ahead of print]

DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.

Pawel M Wydorski, Paulina Macierzynska, Sofia Bali, Jaime Vaquer-Alicea, Lukasz A Joachimiak.

A network of protein folding and degradation machineries maintains protein homeostasis by preventing the accumulation of misfolded proteins and by facilitating their clearance. These systems are also crucial for the inhibition of protein aggregation in neurodegenerative diseases where misfolded proteins often aggregate into β-rich amyloid fibrils. How these machineries selectively recognize pathological aggregates over normal conformations remains unclear. Here, we present the molecular logic for how a Hsp70 co-chaperone from the J-domain protein family, DnaJB1, binds pathological aggregates of the microtubule-associated protein tau through the recognition of the flexible N-terminus that comprises the disordered fuzzy coat of fibrils. We show that this interaction contributes to the regulation of tau assembly in cellular models of tau aggregation and depends on the presence of the negatively charged residues. We determined that DnaJB1 inhibits tau aggregation in vitro through these interactions, and found that this weak, transient binding can be enhanced by the presence of polyanionic factors such as heparin. As prospective client-binding sites, we identified the charged hinge between the two β-sandwich C-terminal domains I and II, as well as the conserved J-domain of this chaperone. This work presents novel biochemical and structural insights into how the molecular chaperone DnaJB1 recognizes full-length forms of tau protein in a pathological context.

DOI: https://doi.org/10.1101/2025.10.02.680111
bioRxiv. 2025 Oct 04. pii: 2025.10.03.680215. [Epub ahead of print]

RiboTRAP-seq identifies spatially distinct functions for the anterior and posterior intestine in immune and metabolic regulation in C. elegans.

Chung-Chih Liu, Nicolas Seban, Supriya Srinivasan.

The intestine integrates food-derived cues to coordinate organismal physiology, yet the molecular specialization of discrete regions along the intestinal epithelium remains unclear. Here, we generate cell type-specific translatomes of the Caenorhabditis elegans intestine during fasting and refeeding using discrete promoters for the anterior quartet of intestinal cells (INT1) and the remaining 8 pairs of intestinal cells (INT2-9). We found that the anterior-most INT1 cells are a translationally distinct intestinal sub-compartment that is particularly enriched for immune- and stress-response genes. Functional assays using novel INT1-specific genes emerging from this study reveal that these specialized cells play a previously unappreciated role in pathogen avoidance and organismal survival. A second critical function of INT1 cells is their role in sensing and responding to the contents of the gut lumen. We show that luminal pyruvate is the key signal linking bacterial nutrients in the gut, to secretion of the gut insulin antagonist INS-7. These findings establish INT1 as sentinel enteroendocrine cells that integrate metabolic and immune cues to couple food status with immune and endocrine responses. Our studies also provide a rich resource for dissecting segment-specific intestinal biology, an overlooked and fertile area for future research.

DOI: https://doi.org/10.1101/2025.10.03.680215
Essays Biochem. 2025 Nov 17. pii: EBC20253033. [Epub ahead of print]

Role of p62 nuclear condensates in regulating ubiquitin-mediated proteasomal degradation.

Chen Lulu-Shimron, Aaron Ciechanover, Victoria Cohen-Kaplan.

  The ubiquitin-proteasome system (UPS) is essential for maintaining cellular proteostasis by selective proteasomal degradation of ubiquitinated proteins. Proper function of the UPS ensures turnover of proteins that have completed their role and removal of damaged proteins. Recent studies have identified p62/Sequestosome-1 as a key modulator of UPS efficiency, particularly through its ability to form dynamic, membraneless condensates via liquid-liquid phase separation. Within the nucleus, these structures recruit and concentrate components of the UPS, including its proteolytic arm - the 26S proteasome and ubiquitinated substrates. This organization enhances substrate recognition and degradation efficiency. Nuclear p62 condensates play an essential role in controlling the turnover of oncogenic proteins. Specifically, they facilitate the proteasomal degradation of the transcription factor c-Myc and prevent its nuclear accumulation by recruiting both c-Myc and its E3 ligase complex SCFFbxw7. Additionally, nuclear p62 condensates contribute to the maintenance of promyelocytic leukemia (PML) nuclear bodies and protect them from stress-induced disassembly by stabilizing the PML protein through sequestration and subsequent degradation of RING Finger Protein 4 (RNF4) - its major E3 ligase. Under stress conditions such as oxidative stress, heat shock, or DNA damage, p62 nuclear condensates rapidly assemble and recruit molecular chaperones and ubiquitin ligases, thereby promoting the clearance of misfolded and damaged proteins. Loss of nuclear p62 or disruption of its condensate-forming domains affects UPS function and compromises proteostasis. These findings highlight the role of p62 condensates in coordinating nuclear protein quality control and protecting cells from proteotoxic and oncogenic stress.

Keywords:  LLPS condensates; p62; proteasome; protein degradation; ubiquitin

DOI:  https://doi.org/10.1042/EBC20253033