Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal–glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress

Proteotoxic stress challenges multiple organelles, but how plants coordinate proteasome capacity with organellar function remains unclear. Langin et al. reveal that endoplasmic reticulum (ER)-associat...

The Lon protease is an important protein degradation machine and is conserved across the three domains of life. Here, the authors describe a small proteotoxic stress-induced protein that functions as ...

Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cort

Proteotoxic stress challenges multiple organelles, but how plants coordinate proteasome capacity with organellar function remains unclear. Langin et al. reveal that endoplasmic reticulum (ER)-associated sorting of NAC53/78 toggles these transcription factors between ER-associated degradation and nuclear activation, coupling proteasome induction to repression of photosynthesis-associated genes during stress.

Proteotoxic stress challenges multiple organelles, but how plants coordinate proteasome capacity with organellar function remains unclear. Langin et al. reveal that endoplasmic reticulum (ER)-associat...

In this review, an integrated conceptual framework linking HSP90's molecular chaperone functions to its pathological roles in cancer is proposed. HSP90 serves as a central node that integrates oncogenic signaling, buffers proteotoxic stress, maintains cancer stem cell plasticity, and shapes tumor-immune interactions, all of which converge to drive therapeutic resistance and tumor recurrence. Within this framework, recent advances are further highlighted in HSP90-targeted interventions, including small-molecule inhibitors, monoclonal antibodies, engineered immune cells, and emerging strategies specifically designed to prevent, delay, or overcome drug resistance and cancer recurrence. ABSTRACT Heat shock protein 90 (HSP90) is an evolutionarily conserved molecular chaperone that occupies a central position in cellular proteostasis and adaptation to stress. By promoting protein folding and facilitating the functional activation of a broad repertoire of clients, HSP90 underpins essential cellular processes, including development, proliferation, differentiation, and stress responses. In cancer, this extensive network renders tumor cells highly dependent on HSP90 to maintain oncogenic signaling, tolerate proteotoxic stress, and survive therapeutic insults. In this review, we propose an integrated conceptual framework linking HSP90's molecular chaperone functions to its pathological roles in cancer: HSP90 serves as a central node that concurrently supports oncogenic signaling, buffers proteotoxic stress, maintains cancer stem cell plasticity, and shapes tumor-immune interactions-all of which converge to drive therapeutic resistance and tumor recurrence. Within this framework, we summarize the molecular mechanisms governing HSP90 activity and dissect its context-dependent roles in cancer progression, drug resistance, and immune regulation. We further highlight recent advances in HSP90-targeted interventions, including small-molecule inhibitors, monoclonal antibodies, engineered immune cells, and emerging strategies designed to prevent, delay, or overcome drug resistance. Taken together, these developments underscore HSP90 as a versatile therapeutic node and point toward innovative, resistance-aware strategies for clinical translation and future research.

Translational regulation is a critical component of the cellular response to environmental stress. Ionizing radiation (IR) exists naturally at low doses (e.g., cosmic rays and radioactive materials) b...

Mitochondrial proteotoxic stress rewires methionine and lipid metabolism in human microglia, driving cellular senescence and disrupting neuronal–glial communication, revealing a mechanism linking mitochondrial dysfunction to brain aging and neurodegeneration.

This study characterizes karyoptosis as a mechanism of neuronal cell death triggered by proteotoxic stress and executed through disintegration of the nuclear lamina, which may account for the death of...

Mitochondrial proteotoxic stress rewires methionine and lipid metabolism in human microglia, driving cellular senescence and disrupting neuronal–glial communication, revealing a mechanism linking mito...

Read the full paper: Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients

Mitochondrial proteotoxic stress rewires methionine and lipid metabolism in human microglia, driving cellular senescence and disrupting neuronal–glial communication, revealing a mechanism linking mito...