bims-cemest 2025-07-13 papers

bims-cemest

Biomed News

on Cell metabolism and stress

Issue of 2025–07–13
twelve papers selected by
Jessica Rosarda, Uniformed Services University

EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress.
The rise of AMPylation: from bacterial beginnings to modern implications in health and disease.
Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
Steroids and one-carbon metabolism: clinical implications in endocrine disorders.
SUMOylation is not a prerequisite for HSF1's role in stress protection and transactivation.
Protein folding success depends on the direction and speed of polypeptide chain appearance.
Organelles share the load.
A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
Autophagic stress activates distinct compensatory secretory pathways in neurons.
Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.
Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline.

Nat Commun. 2025 Jul 07. 16(1): 6247

EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress.

Lei Li, Yufei Lei, Yan Li, Yuxin Xie, Pusheng Hui, Xiaoyan Zang, Weiru Wu, Feng Wu, Jiankun Fan, Jianming Wang, Jieping Chen, Zhe Chen, Yu Hou.

The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.

DOI: https://doi.org/10.1038/s41467-025-61552-0
Biochem Soc Trans. 2025 Jul 08. pii: BST20253056. [Epub ahead of print]

The rise of AMPylation: from bacterial beginnings to modern implications in health and disease.

Meghomukta Mukherjee, Anju Sreelatha.

  Protein AMPylation is a post-translational modification in which adenosine monophosphate (AMP) from ATP is covalently attached to a target protein via a phosphodiester bond. This reaction is catalyzed by AMPylases, a diverse group of enzymes containing adenylyltransferase, filamentation induced by cyclic AMP (FIC), or kinase domains. As a reversible modification, AMPylation is dynamically regulated by both writer enzymes (AMPylases) and eraser enzymes (deAMPylases). Since its initial discovery in bacterial nitrogen metabolism in 1967, AMPylation has been recognized as a critical regulatory mechanism in both prokaryotic and eukaryotic systems. Recent studies link AMPylation to neurological disorders, diabetes, and cancer metastasis, underscoring its physiological and pathological significance. In this review, we present an overview of the discovery of AMPylases and deAMPylases, highlighting their role in cellular signaling, stress response, and host-pathogen interactions.

Keywords:  AMP transferase; FIC domain; adenylylation; post-translational modification; unfolded protein response

DOI:  https://doi.org/10.1042/BST20253056
Sci Adv. 2025 Jul 11. 11(28): eadw1883

Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.

Shruthi Krishnan, Ana Lima, Sizhe Tan, Ying Thong Low, Salvador Perez Montero, Aida Di Gregorio, Adrian Perez Barreto, Sarah Bowling, Karen Vousden, Tristan A Rodriguez.

Cell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that l-proline is a key amino acid sensed by the ISR and that proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified tissue-sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.

DOI: https://doi.org/10.1126/sciadv.adw1883
Neuroendocrinology. 2025 Jul 07. 1-38

Steroids and one-carbon metabolism: clinical implications in endocrine disorders.

Nicolas Scheyer, Rosa-Maria Guéant-Rodriguez, Mikaël Agopiantz, Brigitte Leininger-Muller.

BACKGROUND: One-carbon metabolism (OCM) and steroid metabolism are fundamental biochemical pathways that regulate essential cellular processes and physiological functions. OCM is involved in DNA synthesis, methylation, and redox balance, while steroid metabolism governs the production and degradation of steroid hormones, which influence notably growth, reproduction, and stress responses. Despite their distinct roles, emerging evidence suggests a strong interplay between these two pathways.
SUMMARY: This review examines the bidirectional relationship between OCM and steroid metabolism, emphasizing their shared intermediates and co-factors. Folate and methionine, key components of OCM, influence steroid biosynthesis, while the methylation status regulated by OCM affects the expression of steroidogenic enzymes. Conversely, steroid hormones modulate OCM by altering the activity of enzymes in folate and methionine cycles. Disruptions in either pathway are linked to diseases such as cancer, cardiovascular disorders, and neurodegenerative conditions. This narrative review examines the clinical and pre-clinical data on the interactions between OCM and sex steroids, in both women and men, adrenal steroids and vitamin D metabolism.
KEY MESSAGES: The interdependence between OCM and steroid metabolism highlights the need to consider both pathways in disease pathogenesis and therapeutic strategies. Their crosstalk plays a crucial role in maintaining cellular homeostasis and responding to metabolic stress. Targeting this metabolic interplay offers new opportunities for treating metabolic disorders, with potential clinical applications in modulating one pathway to influence the other for more integrated disease management.

DOI: https://doi.org/10.1159/000547151
Sci Rep. 2025 Jul 05. 15(1): 24077

SUMOylation is not a prerequisite for HSF1's role in stress protection and transactivation.

Miroslav Bardelcik, Oliver Simoncik, Kristina Bednarova, Ondrej Bonczek, Borivoj Vojtesek, Petr Muller.

  Targeting tumor proteostasis has emerged as a promising strategy in anticancer therapy, particularly through Hsp90 inhibition, which has shown clinical potential. However, the efficacy of Hsp90 inhibitors is limited by the activation of HSF1, a master regulator of the heat shock response (HSR), which mitigates proteotoxic stress by inducing protective chaperones. To address this limitation, we investigated the role of HSF1 SUMOylation in modulating its activity and its impact on Hsp90 inhibitor efficacy. We generated HSF1 mutants with lysine-to-arginine substitutions at five SUMOylation sites and studied their function in H1299 lung carcinoma cells with HSF1/HSF2 knockout, which lack a functional HSR. Unexpectedly, these mutants retained full transcriptional activity during the early phase of the heat shock response, mimicking the initial stress response of wild-type HSF1. SUMOylation inhibition using Subasumstat also led to altered nuclear stress bodies morphology but did not impair Hsp70 induction or enhance Hsp90 inhibitor cytotoxicity. Our findings reveal that SUMOylation is dispensable for HSF1 activation and transactivation capacity during the early phase of HSR. These results refine our understanding of HSF1 regulation and suggest that alternative strategies targeting HSF1 stability and degradation may enhance the therapeutic efficacy of proteostasis-targeting cancer therapies.

Keywords:  Cancer; HSF1; Heat shock response; SUMOylation; Stress; Subasumstat

DOI:  https://doi.org/10.1038/s41598-025-08735-3
bioRxiv. 2025 Jul 01. pii: 2025.06.30.662406. [Epub ahead of print]

Protein folding success depends on the direction and speed of polypeptide chain appearance.

Iker F Soto-Santarriaga, Patricia L Clark.

The failure of proteins to fold correctly to their native, functional structures is the molecular basis of many human diseases. Every protein is introduced to the cellular environment from N-to C-terminus as it is synthesized, which can enable the N-terminus to begin folding before the C-terminus appears. Here we show that direction and speed of appearance alone can significantly affect whether a protein will fold to its native structure, versus misfold. This sensitivity demonstrates that folding energy landscapes are sufficiently rugged that conformations adopted by the first portion of the protein to appear can significantly impact subsequent folding steps. Despite high structural similarity, homologous proteins had different sensitivities to vectorial appearance, indicating the native topology is insufficient to determine contours of the energy landscape.

DOI: https://doi.org/10.1101/2025.06.30.662406
Science. 2025 Jul 10. 389(6756): 130-131

Organelles share the load.

Marc Fransen.

Peroxisome-mitochondria contact sites manage mitochondrial oxidative stress.

DOI: https://doi.org/10.1126/science.adz0109
FEBS J. 2025 Jul 07.

A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.

Antigoni Diokmetzidou, Luca Scorrano.

  Organelles were once regarded as discrete entities, but it is now established that they interact through specialized membrane contacts maintained by protein tethers and lipid interactions. Among these, mitochondria-endoplasmic reticulum contact sites (MERCS) emerged as hubs for calcium signaling, lipid metabolism, and mitochondrial dynamics. Here, we critically appraise current methodologies for MERC visualization and quantification, survey the molecular toolbox for their selective perturbation, and highlight common experimental pitfalls. We also discuss key conceptual issues-defining MERCs on structural and functional grounds, addressing redundancy among tethering factors, and distinguishing primary MERC-mediated effects from secondary cellular responses. Finally, we propose that an integrative strategy combining imaging, precise biochemical isolation, proteomics, and functional assays will be essential to resolve outstanding questions about MERC dynamics in physiology and pathology.

Keywords:  endoplasmic reticulum; imaging; membrane contact sites; mitochondria; mitochondria–ER contact sites

DOI:  https://doi.org/10.1111/febs.70184
J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):

MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.

Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.

  Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.

Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH

DOI:  https://doi.org/10.1242/jcs.263701
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2421886122

Autophagic stress activates distinct compensatory secretory pathways in neurons.

Sierra D Palumbos, Jacob Popolow, Juliet Goldsmith, Erika L F Holzbaur.

  Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and aggregated proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay these deleterious effects. Neurons expressing common familial Parkinson's disease-associated mutations in the leucine-rich repeat kinase 2 (LRRK2) exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human induced Pluripotent Stem Cells (iPSC)-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesize that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and live-cell imaging demonstrated that secretory autophagy is upregulated in LRRK2G2019S neurons. We also found that LRRK2G2019S neurons upregulate the release of exosomes containing microRNAs. Live-cell imaging confirmed that this upregulation of exosomal release is dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate secretory autophagy and the compensatory release of exosomes to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to neuroinflammation over the longer term.

Keywords:  Parkinson’s disease; autophagy; neurodegeneration; secretion

DOI:  https://doi.org/10.1073/pnas.2421886122
Adv Sci (Weinh). 2025 Jul 08. e04175

Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.

Francesca Alves, Darius Lane, Adam Wahida, Md Jakaria, Pawel Kalinowski, Adam Southon, Abdel Ali Belaidi, Teresa Samperi-Esteve, Triet Phu Minh Nguyen, Peng Lei, Marcus Krueger, Stefan Mueller, Marcus Conrad, Puja Agarwal, Sue E Leurgans, Julie Schneider, Ashley I Bush, Scott Ayton.

  Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.

Keywords:  ATP; alzheimer's disease; bioenergetics; ferroptosis; glutathione; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1002/advs.202504175
bioRxiv. 2025 Jul 04. pii: 2025.07.01.662628. [Epub ahead of print]

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline.

Sara C Sebag, Tate Neff, Qingwen Qian, Arvand Asghari, Zhuozhi Wang, Zeyuan Zhang, Mark Li, Meihua Hao, Vitor A Lira, Hongli Sun, Matthew J Potthoff, Ling Yang.

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging promotes aberrant BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved BAT senescence, metabolic decline, and cognitive dysfunction in aged mice. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide bioactivity and metabolism in the context of aging.
Highlights: Aging elevates general protein S-nitrosylation while downregulating ADH5 expression in BAT.Loss of thermogenic adipose tissue ADH5 accelerates BAT senescence and exacerbates aging-associated metabolic and cognitive dysfunctions. Disruption of HSF1-activated Adh5 in BAT contributes to aging-associated metabolic and cognitive impairments. Pharmacological targeting of BAT HSF1 alleviates aging-related BAT senescent and systemic declines.

DOI: https://doi.org/10.1101/2025.07.01.662628