bims-proreb 2026-03-01 papers

Issue of 2026–03–01
three papers selected by
Shayan Motiei, Universität des Saarlandes

Methods Cell Biol. 2026 ;pii: S0091-679X(25)00249-3. [Epub ahead of print]203 201-231

Modeling stress-induced proteinopathies in Caenorhabditis elegans.

Elena Caldero-Escudero, Silvia Romero-Sanz.

Proteinopathies are a type of disorders characterized by the intracellular or extracellular accumulation of misfolded proteins that disrupt cellular proteostasis and exert toxic effects. These proteotoxic effects are a common hallmark of various age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and polyglutamine disorders such as Huntington's disease (HD). Misfolded protein accumulation can impair numerous cellular processes, including mitochondrial function, protein degradation pathways, the endoplasmic reticulum stress response, and redox homeostasis, ultimately compromising cell viability. The nematode Caenorhabditis elegans (C. elegans) has emerged as a powerful model for studying proteotoxic stress due to its genetic tractability and the high degree of conservation of key cellular pathways when compared to mammals. These include mitochondrial dynamics and function, regulation of reactive oxygen species (ROS), and the cellular capacity to manage protein aggregates in terms of number, size, and clearance efficiency. The integration of these conserved stress response pathways together with C. elegans experimental versatility positioned this nematode as an ideal system to investigate the molecular mechanisms underlying proteinopathy-induced toxicity. In this chapter, we describe a set of complementary methodologies to evaluate proteotoxic stress in C. elegans models of protein misfolding. These include assays to measure mitochondrial reactive oxygen species (ROS) and membrane potential (Δψm), analyses of mitochondrial morphology and oxygen consumption, protein extraction protocols, and in vivo staining and semi-automated quantification of protein aggregates.

Keywords: Aggregates; C. elegans; Mitochondria; Proteinopathy; Protocols; Toxicity

DOI: https://doi.org/10.1016/bs.mcb.2025.12.007

bioRxiv. 2026 Feb 12. pii: 2026.02.10.705198. [Epub ahead of print]

Mild Mitochondrial Impairment Activates Overlapping Longevity Pathways Converging on the Flavin-Containing Monooxygenase FMO-2.

Jeremy M Van Raamsdonk.

A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of fmo-2 in the long lifespan of genetic mitochondrial mutants in C. elegans . We found that fmo-2 , but not other fmo genes, are specifically upregulated in the long-lived mitochondrial mutants clk-1, isp-1 and nuo-6 . Disruption of fmo-2 through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that fmo-2 is required for lifespan extension in these worms. Moreover, signaling molecules that have been shown to be involved in upregulation of fmo-2 are also required for the long life of clk-1, isp-1 and nuo-6 mutants including HLH-30, NHR-49 and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in clk-1 mutants on the expression of fmo-2 . We found that in all cases, genes required for clk-1 longevity are also required for the upregulation of fmo-2 in clk-1 worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.

DOI: https://doi.org/10.64898/2026.02.10.705198

Nat Commun. 2026 Feb 23.

Membrane-embedded polar residues target membrane proteins for degradation by the quality control protease FtsH.

Michal Chai-Danino, Noy Ravensary-Modin, Vasiliy I Vladimirov, Tetiana Onyshchuk, Martin Plöhn, Alon B D Barshap, Aseel Bsoul, Hadas Peled-Zehavi, Nir Fluman.

The biogenesis of membrane proteins (MPs) is inherently error-prone, and is therefore monitored by quality control mechanisms that remove faulty MPs. A key challenge for this surveillance is to recognize misfolded MPs, but how this is achieved remains poorly understood. Here we reveal how FtsH, the main MP quality control protease in Escherichia coli, specifically targets faulty MPs. By analyzing the in vivo degradation of two substrates, we show that lipid-facing polar residues trigger FtsH-mediated degradation. In folded MPs, such polar residues are usually buried in the protein core. Their exposure to the membrane can therefore signal misfolding and promote degradation. Strikingly, lipid-facing polar residues can even trigger degradation of a folded protein, and do not require the extended cytosolic regions typically needed for other FtsH substrates. Recognition depends on the FtsH transmembrane domain and on specific polar residues within it. Thus, sensing misfolding within the membrane helps maintain the integrity of the membrane proteome.

DOI: https://doi.org/10.1038/s41467-026-69829-8