bims-mihora 2025-10-26 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–10–26
eight papers selected by
Lisa Patel, Istesso Limited

The role of the fibroblast in cardiorenal syndrome.
Modulation of stress responses in C. elegans: Sex differences and neuronal control.
ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.
Reductive Stress and Dysregulated Energy Metabolism in Schizophrenia: Mechanisms and Therapeutic Targets.
Signal Relay in C. elegans: A Tissue-Perspective on Coordinating Organismal Proteostasis and its Impact on Aging.
The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.
Senescent fibroblasts modulate the radiation response of neighboring epithelial cells.
Collagen I Derived Extracellular Matrix Motifs Alter Fibroblast Regenerative Response.

Am J Physiol Cell Physiol. 2025 Oct 20.

The role of the fibroblast in cardiorenal syndrome.

Karin Åvall, Julie M Williams.

  The diversity of fibroblasts across different organs, and within the same structures, means that their role in both health and disease is manifold. This review focusses on their job in the heart and kidney, specifically during the course of cardiorenal syndrome (CRS). During CRS there is a complex bidirectional interplay between the two body systems whereby the failure of one drives the decline of the other. These effects are manifest by a response that leads to the deposition of fibrotic tissue, attributable to fibroblast dysfunction. Fibroblasts in themselves provide essential functions within organs, which are determined by the specific identity of their subtype. During disease fibroblast function is further constrained and directed by the niches that form at the sites of injury. This review delves into the origins of fibroblasts in heart and kidney, their functions in each tissue and the processes and stressors whereby they become activated to form myofibroblasts. We discuss tools that can be used to study the phenomenon of fibroblast activation in vitro and in human studies and, finally, what therapeutic possibilities there may be in the future.

Keywords:  Cardiorenal syndrome; fibroblasts; fibrosis; heart; kidney

DOI:  https://doi.org/10.1152/ajpcell.00441.2025
Curr Opin Neurobiol. 2025 Oct 17. pii: S0959-4388(25)00159-X. [Epub ahead of print]95 103128

Modulation of stress responses in C. elegans: Sex differences and neuronal control.

Arantza Barrios.

The effect of stress on an organism can be diverse and systemic, impacting cell physiology, development and behaviour. Here, I review the molecular mechanisms by which stressors (noxious stimuli) negatively impact all these aspects of animal biology and some of the mechanisms employed by the organism to combat damage by such insults. I focus on research carried out in the nematode Caenorhabditis elegans and the stress response pathways that enhance the core proteostasis network, a collection of molecular chaperones and degradation factors that refold or remove damaged proteins. Insults are often sensed by the nervous system, which then triggers stress response pathways systemically in distal tissues. Inter-tissue communication for cell nonautonomous regulation of stress responses by the nervous system involves many different neurotransmitters and modulators in an insult-specific manner. Sex-specific differences in stress sensitivity and proteostasis strategies also exist, with males generally being more resilient than hermaphrodites. However, male reproductive development and behaviour remain particularly vulnerable to stress.

DOI: https://doi.org/10.1016/j.conb.2025.103128
Cell Death Dis. 2025 Oct 21. 16(1): 741

ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.

Teresa T Liu, Mia J Carrarini, Livianna K Myklebust, Kegan O Skalitzky, Nathalie El-Khoury, Ian J Sipula, Alexander Chang, Vishal Soman, Ailing Liu, Nnamdi Ihejirika, Uma R Chandran, Michael J Jurczak, William A Ricke, Donald B DeFranco, Laura E Pascal.

Declining mitochondrial function is an established feature of aging and contributes to most aging-related diseases through its impact on various pathologies such as chronic inflammation, fibrosis and cellular senescence. Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD+/NADH ratio, and reduced CI function in BHPrS1 cells. Thus, ZC3H4 loss promotes mitochondrial dysfunction to drive pathophysiologic changes in the stromal compartment that are features of the aging prostate.

DOI: https://doi.org/10.1038/s41419-025-08027-8
Biol Psychiatry. 2025 Oct 16. pii: S0006-3223(25)01528-8. [Epub ahead of print]

Reductive Stress and Dysregulated Energy Metabolism in Schizophrenia: Mechanisms and Therapeutic Targets.

Onur Memetoglu, Fei Du, Virginie-Anne Chouinard, Dost Ongur.

  Reductive stress, defined by excessive accumulation of reducing equivalents, such as NADH, disrupts cellular redox balance and is emerging as a detrimental factor in schizophrenia (SZ). It is closely related to the mitochondrial defects commonly seen in SZ, which implies its importance in impaired energy metabolism. Reductive stress intersects with oxidative stress pathways and causes an underappreciated additional burden on cellular systems. The Integrated Stress Response (ISR) is an adaptive pathway, typically activated by mitochondrial oxidative phosphorylation (OxPhos) defects and other stressors. Emerging evidence indicates that reductive stress can independently activate the ISR. These findings highlight the crucial role of reductive stress in disease pathophysiology, although the process, to a great extent, is not fully understood. Hence, there is a need for innovative therapeutic approaches that can address reductive stress and mitochondrial dysfunction.

Keywords:  Energy Metabolism; Mitochondrial Dysfunction; NAD(+)/NADH Imbalance; Oxidative Phosphorylation; Reductive Stress; Schizophrenia

DOI:  https://doi.org/10.1016/j.biopsych.2025.10.008
Cell Stress Chaperones. 2025 Oct 18. pii: S1355-8145(25)00072-0. [Epub ahead of print] 100127

Signal Relay in C. elegans: A Tissue-Perspective on Coordinating Organismal Proteostasis and its Impact on Aging.

Loren Cocciolone, Akhil Souparnika, Valeria Uvarova, Katie Kessler, Patricija van Oosten-Hawle.

  As the global demographics shifts towards an increasingly aging population, understanding the effects and molecular mechanisms underlying aging becomes more and more important within biomedical research. A hallmark of aging is the progressive deterioration of protein homeostasis (proteostasis), characterized by the accumulation of misfolded protein aggregates within the cell. The proteostasis network is essential in mitigating the harmful effects of proteotoxic aggregates by activating stress response and degradation pathways. Significant discoveries in aging research are often inherently intertwined with proteostasis, many of which were made using the invertebrate Caenorhabditis elegans. Many longevity pathways, such as the insulin-like signaling pathway, initially identified in C. elegans, are mediated through inter-tissue stress signaling from the nervous system, intestine, or gonad. These cell nonautonomous signaling pathways not only enhance lifespan and stress resilience but also limit age-related accumulation of protein aggregates that exacerbate age-associated diseases. Thus, findings from aging research were often key to providing new insights into cell nonautonomous regulation of stress responses and organismal proteostasis. In this review, we outline key discoveries made using C. elegans as a model system and highlight their contributions that led to our current understanding of inter-tissue communication in organismal proteostasis regulation. We furthermore highlight emerging concepts and discuss the translational relevance of conserved cell nonautonomous proteostasis regulation in mammals. We emphasize the importance of mammalian research to support the research done in C. elegans, with the future goal of developing potential therapeutic interventions targeting these inter-tissue proteostasis signaling pathways to combat aging.

Keywords:  Aging; Intestine; Lipid Metabolism; Nervous System; Neurodegenerative Diseases; Organismal Proteostasis; Proteotoxicity; Reproductive System; Transcellular Stress Signaling

DOI:  https://doi.org/10.1016/j.cstres.2025.100127
Redox Biol. 2025 Oct 08. pii: S2213-2317(25)00397-0. [Epub ahead of print]87 103884

The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.

Christine Zarges, Hanna Fieler, Robin Alexander Rothemann, Simon Poepsel, Lucas T Jae, Jan Riemer.

  The mitochondrial disulphide relay is the key machinery for import and oxidative protein folding in the mitochondrial intermembrane space. Among IMS proteins with unknown function, we identified FAM136A as a new substrate of the mitochondrial disulphide relay. We demonstrate a transient interaction between FAM136A and MIA40, and that MIA40 introduces four disulphide bonds in two twin-CX3C motifs of FAM136A. Consequently, IMS import of FAM136A requires these cysteines and its steady state levels in intact cells are strongly dependent on MIA40 and AIFM1 levels. Furthermore, we show that FAM136A forms non-covalent homodimers as a mature protein. Acute deletion of FAM136A curtails cellular proliferation capacity and elicits a robust induction of the integrated stress response, coincident with the aggregation and/or depletion of selected IMS proteins including HAX1 and CLPB. Together, this establishes FAM136A as a pivotal component of the IMS proteostasis network, with implications for overall cellular function and health.

Keywords:  FAM136A; Integrated stress response; MIA40; Oxidative protein folding

DOI:  https://doi.org/10.1016/j.redox.2025.103884
Cell Death Discov. 2025 Oct 20. 11(1): 468

Senescent fibroblasts modulate the radiation response of neighboring epithelial cells.

Maja Buchholzki, Lisa Marie Stasch, Bettina Budeus, Vaanilaa Ketheeswaranathan, Zehra Fatma Sevindik, Verena Jendrossek, Diana Klein.

Radiation-induced lung injury (RILI) not only limits the therapeutic dose that can be administered during chest and thorax radiotherapy (RT), but also significantly impairs patients' health and quality of life. RT-induced senescence and the associated altered secretory profile, the senescence-associated secretory phenotype (SASP), have emerged as a central process for the development and progression of pneumonitis and pulmonary fibrosis. Among various lung cell types, the phenomenon of permanent cell cycle arrest, which is also accompanied by significant morphological changes, has been observed especially in epithelial cells. RILI arises from a complex interplay of cell types and signaling pathways, but it has not yet been clarified when which lung cell types become senescent during RT and how induced changes in one cell type may influence senescence or the RT-dependent cell fate overall in another, adjacent cell type. Here, the different cellular fates particularly senescence versus apoptotic cell death following RT-induced genotoxic stress were investigated particularly in epithelial cells and fibroblasts providing further insights into the radiosensitivity of these lung cells. Fibroblasts that have become senescent during RT alter the RT response and thus the cell fate of co-cultured epithelial cells. In addition, new candidate genes were identified that were induced in the various cellular subpopulations of complex epithelial-fibroblast spheroids as an approximate in vivo cell culture model after irradiation. These candidate genes could be used in future studies as additional RT-induced gene sets and, in particular, as senescence-associated gene sets. A comprehensive understanding of the dynamic changes of these cellular components is crucial to specify new strategies for the prevention of RILI.

DOI: https://doi.org/10.1038/s41420-025-02796-z
Cells Tissues Organs. 2025 Oct 20. 1-23

Collagen I Derived Extracellular Matrix Motifs Alter Fibroblast Regenerative Response.

Opemipo Sanyaolu, Victoria Garza, Athena Santi, Gabriela Romero Uribe, Teja Guda, Alisa Isaac.

Introduction Damage-associated molecular patterns, or DAMPs, are molecules released in response to tissue or cellular damage to facilitate tissue regeneration. This inflammatory response can occur in sterile environments and is promoted by the release of damaged extracellular components such as the extracellular matrix. DAMPs have been implicated in various stages of wound healing but have yet to be explicitly utilized for regenerative medicine by leveraging selective modulation of the inflammatory response. With this in mind, we leverage inflammation to drive tissue regeneration by utilizing DAMPs collected from the native extracellular matrix, extracellular matrix motifs (mECM). Methods Here, mECMs were derived from UV-damaged rat tail collagen I. Fibroblast response to various concentrations and presentation of mECMs was investigated by evaluating changes in viability, proliferation, cell phenotype, and cytokine secretion. Results mEMCs had reduced intensity in collagen I associated bands, indicating successful fragmentation to lower molecular weights. Soluble free mECMs induced changes in fibroblast phenotype as indicated by a decrease in proliferation, decrease in nuclei area, and increase in percentage of elongated cells. In addition, free mECMs contributed to significant increases in cytokine secretion compared to insoluble bound mECMs. Across all experiments, bound mECMs exhibited effects on fibroblasts compared to the collagen control Conclusion Fibroblasts in vitro recognize mECMs, with significant differences observed based on the presentation of these proteins. This data indicates that cryptic regions that are recognized by fibroblasts may be exposed in the free version of the mECMs, which lead to a myofibroblast-like phenotype in fibroblasts. This work highlights the potential of DAMPs to serve as immunomodulatory therapeutics for tissue regeneration.

DOI: https://doi.org/10.1159/000549101