bims-proreb Biomed News
on Proteostasis and redox biology
Issue of 2025–12–07
nine papers selected by
Shayan Motiei, Universität des Saarlandes
  1. Conservation of mRNA operon formation in control of the heat shock response in mammalian cells.
  2. Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
  3. Engineering ATP Import in Yeast Uncovers a Synthetic Route to Extend Cellular Lifespan.
  4. The transcription factor SKN-1 drives lysosomal enlargement during aging to maintain function.
  5. Nucleosome stability safeguards cell identity, stress resilience and healthy aging.
  6. Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.
  7. Molecular mechanisms of the lysosomal damage response and its roles in aging and disease.
  8. Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.
  9. The Rieske iron-sulfur protein is a primary target of molecular hydrogen.
  1. Sci Adv. 2025 Dec 05. 11(49): eadu0315
    Conservation of mRNA operon formation in control of the heat shock response in mammalian cells.
    Emese Pataki, Jeffrey E Gerst.
      Prokaryotes use polycistronic transcription (operons) to express multiple messenger RNAs (mRNAs) from a single promoter to coexpress functionally related genes. However, how do eukaryotes, which express monocistronic messages, achieve the same regulation? Previously, we demonstrated that yeast uses RNA operons, i.e., mRNAs assembled in trans (transperons), to control multiple cellular pathways such as the heat shock response (HSR). As the HSR is conserved from yeast to mammals, we used single-molecule RNA labeling and pulldown techniques to demonstrate that mammalian heat shock protein (HSP) mRNAs also form operons upon transcription during heat stress. HSP RNA operon formation is dependent on the heat shock factor 1 transcription factor and intra- and interchromosomal interactions between the HSP genes. Work in yeast identified a conserved RNA sequence motif and histone H4 functions that act downstream thereof to regulate transperon assembly. Our work highlights the evolutionarily conserved regulation of the HSR and for RNA operons in eukaryotic gene regulation.
    DOI:  https://doi.org/10.1126/sciadv.adu0315
  2. Nat Commun. 2025 Dec 01. 16(1): 10817
    Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
    Mrityunjoy Mondal, Enzo Scifo, Rossella Erminia Ciliberti, Lena Wischhof, Tannaz Norizadeh Abbariki, Joshua Jackson, Ioanna-Maria Menegatou, Viktoria Zeisler-Diehl, Jan Riemer, Benjamin Jussila, Christopher E Hopkins, Sylwia Kierszniowska, Lukas Schreiber, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
      Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1038/s41467-025-66900-8
  3. bioRxiv. 2025 Nov 17. pii: 2025.04.14.648769. [Epub ahead of print]
    Engineering ATP Import in Yeast Uncovers a Synthetic Route to Extend Cellular Lifespan.
    Naci Oz, Hetian Su, Vedat Sari, Praveen Patnaik, Rohil Hameed, Jong Hee Song, Derek C Prosser, Vyacheslav M Labunskyy, Vadim N Gladyshev, Nan Hao, Alaattin Kaya.
      Aging results from the gradual accumulation of molecular damage as a result of cellular processes and is characterized by impaired functions, most notably an age-related decline in ATP production. However, the causal relationship between cellular ATP homeostasis and aging has not been established. In this study, we used a novel approach by harnessing a nucleotide transporter from a eukaryotic intracellular parasite to facilitate the direct import of extracellular ATP into budding yeast cells, enabling us to effectively manipulate their intracellular ATP levels. We found that depletion of ATP significantly reduces lifespan, while the supplementation of ATP in the growth medium fully restores it thereby extending lifespan. Moreover, gene expression analysis revealed that elevated ATP levels inhibit catabolic processes, indicating a suppression of glucose metabolism. Overall, our study revealed the direct impact of cellular ATP homeostasis on lifespan regulation that has never been directly tested before. This work offers new insights into the bioenergetic control of aging and positions energy metabolism as a promising target for longevity interventions.
    Significance: Cellular energy homeostasis is a crucial factor in determining the health and longevity of organisms. While intracellular ATP levels are tightly regulated, the idea that cells can directly take in extracellular ATP to influence metabolism has not been thoroughly explored. In this study, we engineered yeast cells to import external ATP and demonstrated that this approach significantly alters mitochondrial function, metabolic flow, and aging processes. Our findings show that ATP uptake inhibits catabolic pathways and enhances mitochondrial maintenance, thereby extending cellular lifespan through a novel and non-traditional mechanism. This research reveals an unexpected degree of metabolic flexibility and introduces a synthetic biology-based method to reprogram energy metabolism and longevity. The principles established in this study provide a new framework for understanding the role of cellular bioenergetics in aging, highlighting how the modulation of ATP availability can impact metabolic states and lifespan regulation.
    DOI:  https://doi.org/10.1101/2025.04.14.648769
  4. PLoS Biol. 2025 Dec 05. 23(12): e3003540
    The transcription factor SKN-1 drives lysosomal enlargement during aging to maintain function.
    Xinyu Wang, Huimin Liu, Xiaoman Wang, Ben Zhou, Haiqing Tang, Shanshan Pang.
      Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes. Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.
    DOI:  https://doi.org/10.1371/journal.pbio.3003540
  5. Res Sq. 2025 Nov 18. pii: rs.3.rs-7913970. [Epub ahead of print]
    Nucleosome stability safeguards cell identity, stress resilience and healthy aging.
    Peter Adams, Hiroshi Tanaka, Brenna McCauley, Clara Guida, Xue Lei, Sha Li, Tatiana Moreno, K'leigh Guillotte, Zong Chua, Adrianna Abele, Aashna Lamba, Rouven Arnold, Adarsh Rajesh, Marcos Teneche, Laurence Haddadin, Anagha Deshpande, Aniruddha Deshpande, Alexandre Colas, Caroline Kumsta, Michael Petrascheck, Rolf Bodmer, Weiwei Dang.
      The Information Theory of Aging (ITOA) proposes that aging results from the progressive loss of epigenetic information. As the repeating units of the epigenome, nucleosomes are considered pivotal for its stability. Accordingly, the ITOA predicts that destabilization of nucleosomes will accelerate aging. However, this causal link has not been directly tested. Here, we addressed this through histone mutants that weaken histone-histone interactions. Without broadly perturbing steady-state chromatin accessibility, DNA damage, cell proliferation or viability, nucleosome instability compromised cell identity maintenance, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-including environmental, epigenetic and mitotic stress-in human cells and Saccharomyces cerevisiae. These cross-species findings establish nucleosome stability as a fundamental requirement for preserving cell identity and stress resilience, thereby safeguarding organismal longevity.
    DOI:  https://doi.org/10.21203/rs.3.rs-7913970/v1
  6. bioRxiv. 2025 Nov 18. pii: 2025.11.17.688722. [Epub ahead of print]
    Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.
    David K Sidibe, Erin M Smith, Maeve L Spivey, Maria C Vogel, Sandra Maday.
      Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.
    DOI:  https://doi.org/10.1101/2025.11.17.688722
  7. J Cell Sci. 2025 Dec 01. pii: jcs264255. [Epub ahead of print]138(23):
    Molecular mechanisms of the lysosomal damage response and its roles in aging and disease.
    Shuhei Nakamura, Takayuki Shima, Tamotsu Yoshimori.
      Lysosomes are the main digestive organelles and serve as a signaling hub linking environmental cues to cellular metabolism. Through these functions, lysosomes play a crucial role in maintaining cellular and organismal homeostasis. However, how lysosomal homeostasis itself is maintained is not well understood. Lysosomes are frequently damaged by a variety of substances, including crystals, silica, lipids, bacteria, toxins, amyloid proteins and reactive oxygen species. When lysosomes are damaged, their acidic contents leak out, leading to oxidative stress, inflammation and cell death. Damaged lysosomes are thus harmful to cells, and to restore lysosomal function after damage, cells have developed several defense mechanisms, collectively called the lysosomal damage response (or endo-lysosomal damage response). Recent studies have shown that this response is composed of three main pathways depending on the degree and duration of damage - repair, removal of the damaged lysosomes, and lysosomal biogenesis and regeneration. Growing evidence suggest that the failure and/or dysregulation of this response is implicated in aging and several diseases, including neurodegenerative diseases and kidney disease. In light of the rapid growth of this field, this Review summarizes our current knowledge of the lysosomal damage response, its significance in aging and diseases, and future perspectives.
    Keywords:  Aging; Autophagy; Disease; Lysosomal damage; Lysosome
    DOI:  https://doi.org/10.1242/jcs.264255
  8. Nat Commun. 2025 Dec 02. 16(1): 10842
    Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.
    Anna Platzek, Klára Odehnalová, Julia P Schessner, Georg H H Borner, Sebastian Schuck.
      Sophisticated techniques are available for systematic studies of yeast cell biology. However, it remains challenging to investigate protein subcellular localization changes on a proteome-wide scale. Here, we apply Dynamic Organellar Mapping by label-free mass spectrometry to detect localization changes of native, untagged proteins during endoplasmic reticulum (ER) stress. We find that hundreds of proteins shift between cellular compartments. For example, we show that numerous secretory pathway proteins accumulate in the ER, thus defining the extent and selectivity of ER retention of misfolded proteins. Furthermore, we identify candidate cargo proteins of the ER reflux pathway, determine constituents of reticulon clusters that segregate from the remainder of the ER and provide evidence for altered nuclear pore complex composition and nuclear import. These findings uncover protein relocalization as a major aspect of cellular reorganization during ER stress and establish Dynamic Organellar Maps as a powerful discovery tool in yeast.
    DOI:  https://doi.org/10.1038/s41467-025-66946-8
  9. Redox Biol. 2025 Nov 27. pii: S2213-2317(25)00465-3. [Epub ahead of print]88 103952
    The Rieske iron-sulfur protein is a primary target of molecular hydrogen.
    Shuto Negishi, Mikako Ito, Tomoya Hasegawa, Hikaru Otake, Bisei Ohkawara, Akio Masuda, Hiroyuki Mino, Tyler W LeBaron, Kinji Ohno.
      The mechanisms underlying the biomedical effects of molecular hydrogen (H2) remain poorly understood and are often attributed to its selective reduction of hydroxyl radicals, based on the long-held notion that H2 is biologically inert. We demonstrate that H2 is biologically active, specifically targeting the Rieske iron-sulfur protein (RISP). We first observed that H2 induces the mitochondrial unfolded protein response (UPRmt) in cultured cells exposed to H2 and in mouse liver after H2 water administration. H2 suppressed electron transport chain complex III activity in mouse liver homogenates to 78.5 % within 2 min. Given the evolutionary link with hydrogenases, we examined RISP as a potential target of H2. We found that H2 promotes RISP degradation within 1 h in cultured cells by activating mitochondrial Lon peptidase 1 (LONP1). Loss of RISP and subsequent UPRmt induction may explain the pleiotropic and paradoxical effects of H2. These findings identify RISP as a primary target of H2, demonstrating that H2 is biologically active as a signaling molecule.
    Keywords:  Hydrogenase; Mitochondrial unfolded protein response; Molecular hydrogen; Rieske iron-sulfur protein
    DOI:  https://doi.org/10.1016/j.redox.2025.103952
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