bims-proreb 2026-02-01 papers

Issue of 2026–02–01
five papers selected by
Shayan Motiei, Universität des Saarlandes

Aging Cell. 2026 Feb;25(2): e70399

Reduced Proteasome Degradation of HSF-1 Shifts Protein Stress Management With Age in Caenorhabditis elegans.

Hongwei Wang, Fengzhen Sun, Zhidong He, Xiaojie Wang, Hao Liu, Mengjiao Song, Qingxia Chen, Zhixue Li, Ligang Wu, Xiumin Yan, Xueliang Zhu, Yidong Shen.

To maintain protein homeostasis, which is essential for health, animals have developed complex protective mechanisms against various acute and chronic stresses. However, the coordination of responses to these protein stresses, especially their age-dependent changes, is not well understood. HSF-1 is a key regulator of protein homeostasis. Our study identifies PBS-7, a proteasome subunit, as its crucial regulator. In aged C. elegans, decreased PBS-7 binding reduces proteasome-mediated degradation of HSF-1. The increase in HSF-1 enhances responses to chronic stresses, like accumulating protein aggregates, by upregulating heat shock proteins (HSPs) and autophagy genes. Meanwhile, the upregulated HSPs suppress the activation of HSF-1 upon acute stress, such as heat shock. Our findings reveal a mechanism that coordinates responses to acute and chronic protein stresses and highlights an adaptation prioritising protection against increasing protein aggregates in ageing.

Keywords: HSF‐1; proteasome; stress resistance

DOI: https://doi.org/10.1111/acel.70399

FEBS J. 2026 Jan 29.

ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.

Giorgia Maria Renna, Alessandro Cherubini, Ersilia Varone, Serena Germani, Alice Marrazza, Ester Zito.

Proteostasis maintains the balance between protein synthesis, folding, and degradation within the endoplasmic reticulum (ER). This quality-control system ensures that proteins undergo proper post-translational modifications-such as PDI-ERO1-mediated oxidative folding and STT3-dependent N-glycosylation-so that only correctly folded proteins proceed through the secretory pathway. Impairment of protein load, folding capacity, or degradation via the ER-associated degradation (ERAD) pathway leads to the accumulation of unfolded proteins, triggering ER stress and activating the unfolded protein response (UPR), which, in the first instance, is an adaptive signaling network designed to restore homeostasis by adjusting protein synthesis, enhancing folding capacity, and promoting the clearance of misfolded proteins. During ER stress, the ER undergoes morphological and functional remodeling to manage the increased folding burden, including an increase of ER-mitochondria contact sites (ERMCs). These nanometric junctions (~10-100 nm) facilitate lipid and metabolite exchange and mediate calcium and reactive oxygen species signaling to support cellular metabolism. However, chronic ER stress can further tighten ERMCs, leading to calcium overload, mitochondrial dysfunction, and apoptosis. This review examines the core mechanisms underlying ER proteostasis in the context of ER stress and explores how ER stress first boosts mitochondrial activity and later impairs it through ERMCs, contributing to cell death and disease. Finally, emerging therapeutic strategies aimed at restoring proteostasis and modulating the dynamics of ERMCs are highlighted as promising interventions for conditions, such as cancer and congenital myopathies, where ER and mitochondrial dysfunction play central roles in pathogenesis.

Keywords: ERMC; cancer; mitochondria metabolism; neuromuscular diseases; proteostasis

DOI: https://doi.org/10.1111/febs.70431

Front Aging Neurosci. 2025 ;17 1713391

The aggregate proteome of Caenorhabditis elegans mitochondria implicates shared mechanisms of aging and Alzheimer's disease.

Sonu Pahal, Akshatha Ganne, Meenakshisundaram Balasubramaniam, Sue T Griffin, Robert J Shmookler Reis, Srinivas Ayyadevara.

Background: Mitochondrial dysfunction and protein aggregation are central features of brain aging and Alzheimer's disease (AD). To define how AD seed proteins modulate these processes, we applied quantitative proteomics to sarkosyl-insoluble aggregates from C. elegans models of normal aging and from worms expressing human Aβ or Tau transgenes.
Results: Normal aging produced a late-onset accrual of mitochondrial proteins within aggregates, implicating impaired energy metabolism and proteostasis collapse. Aβ expression caused a striking expansion and included glycolytic enzymes, tricarboxylic acid cycle components, ribosomal proteins, and trafficking factors, consistent with broad proteostatic and bioenergetic stress, largely overlapping with aging-associated species, yet advanced in onset. Tau expression yielded a smaller set enriched for cytoskeletal, vesicular, and nuclear pore components. Post-translational modifications (4-HNE adducts, phosphorylation, acetylation, methionine oxidation) revealed distinct trajectories: Aβ imposed early oxidative and phosphorylation burden, whereas Tau and aging showed midlife PTM peaks consistent with delayed proteostasis collapse. Cross-species comparison revealed 68 insoluble proteins shared between worm models and human AD brain aggregates. From these, 17 conserved metabolic, chaperone, and trafficking proteins were prioritized by network metrics and validated functionally: RNAi knockdowns aggravated paralysis or impaired chemotaxis, confirming their functional importance.
Conclusion: These findings place mitochondrial proteome collapse at the center of aging and AD-seeded pathology, distinguish Aβ- and Tau-driven proteotoxic routes, and nominate a conserved panel of aggregation-prone proteins as mechanistic drivers and candidate biomarkers for early detection and intervention in AD.

Keywords: Alzheimer disease; Caenorhabditis elegans; aging; biomarkers; mitochondria; neurodegeneration; protein aggregation; proteomics

DOI: https://doi.org/10.3389/fnagi.2025.1713391

Antioxidants (Basel). 2025 Dec 24. pii: 29. [Epub ahead of print]15(1):

Redox Regulation of Complement Pathway Activation in Aging and Related Diseases.

Shirin Ferdowsi, Srividya Arjuna, Sudharshan Sj, Rahima Zennadi.

Aging is a complex degenerative process characterized by the accumulation of molecular damage and a heightened susceptibility to disease. The oxidative stress theory of aging identifies endogenous reactive oxygen species (ROS) as primary drivers of this cellular deterioration. This review provides a comprehensive analysis of the critical, yet underappreciated, interplay between oxidative stress and the complement system, a powerful effector of innate immunity. We detail the mechanistic pathways through which redox imbalance directly activates complement components and, conversely, how complement activation amplifies oxidative stress, creating a vicious cycle that accelerates tissue damage. A central focus is placed on how this redox-complement axis contributes to the pathophysiology of age-related conditions, including neurodegenerative, cardiovascular, and metabolic diseases. Furthermore, the review explores emerging therapeutic strategies that target this interaction, highlighting the potential of antioxidant and complement-inhibitory approaches to disrupt this cycle and promote healthy aging. By synthesizing current evidence, this work underscores the significance of the redox-complement network as a key mechanistic link in aging and its associated diseases.

Keywords: aging; complement activation; complement system; oxidative damage; oxidative stress; reactive oxygen species

DOI: https://doi.org/10.3390/antiox15010029

Antioxidants (Basel). 2025 Dec 31. pii: 54. [Epub ahead of print]15(1):

Dynamic Oxidative States: Interplay of Aging, Metabolic Stress, and Circadian Rhythms in Modulating Stroke Severity.

Jui-Ming Sun, Jing-Shiun Jan, Cheng-Ta Hsieh, Rajeev Taliyan, Chih-Hao Yang, Ruei-Dun Teng, Ting-Lin Yen.

Oxidative stress is a defining feature of stroke pathology, but the magnitude, timing and impact of redox imbalance are not static. Emerging evidence indicates that physiological contexts, such as aging, metabolic stress, and circadian disruption, continuously reshape oxidative status and determine the brain's vulnerability to ischemic and reperfusion injury. This review integrates recent insights into how these intrinsic modulators govern the transition from adaptive physiological redox signaling to pathological oxidative stress during stroke. Aging compromises mitochondrial quality control and blunts NRF2-driven antioxidant responses, heightening susceptibility to ROS-driven damage. Metabolic dysfunction, as seen in obesity and diabetes, amplifies oxidative burden through NADPH oxidase activation, lipid peroxidation, and impaired glutathione recycling, further aggravating post-ischemic inflammation. Circadian misalignment, meanwhile, disrupts the rhythmic expression of antioxidant enzymes and metabolic regulators such as BMAL1, REV-ERBα, and SIRT1, constricting the brain's temporal window of resilience. We highlight convergent signaling hubs, NRF2/KEAP1, SIRT-PGC1α, and AMPK pathways, as integrators of these physiological inputs that collectively calibrate redox homeostasis. Recognizing oxidative stress as a dynamic, context-dependent process reframes it from a static pathological state to a dynamic outcome of systemic and temporal imbalance, offering new opportunities for time-sensitive and metabolism-informed redox interventions in stroke.

Keywords: AMPK; NRF2; SIRT1; aging; circadian rhythm; metabolic stress; mitochondrial dysfunction; oxidative stress; redox homeostasis; stroke

DOI: https://doi.org/10.3390/antiox15010054