bims-cemest 2025-03-02 papers

bims-cemest

Biomed News

on Cell metabolism and stress

Issue of 2025–03–02
23 papers selected by
Jessica Rosarda, Uniformed Services University

RNA exosome-driven RNA processing instructs the duration of the unfolded protein response.
PERK-Olating Through Cancer: A Brew of Cellular Decisions.
Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease.
ISR Modulators in Neurological Diseases.
An In Vitro System to Study Mammalian GCN2 Regulation.
Protein degradation and growth dependent dilution substantially shape mammalian proteomes.
Lysosomal degradation of ER client proteins by ER-phagy and related pathways.
Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus.
TIM8 Deficiency in Yeast Induces Endoplasmic Reticulum Stress and Shortens the Chronological Lifespan.
Endoplasmic reticulum stress inhibition preserves mitochondrial function and cell survival during the early onset of isoniazid-induced oxidative stress.
Small Heat Shock Proteins: Protein Aggregation Amelioration and Neuro- and Age-Protective Roles.
In Vitro Inhibition of Endoplasmic Reticulum Stress: A Promising Therapeutic Strategy for Patients with Crohn's Disease.
Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.
Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.
HSF1 Mediates Palmitic Acid-Disrupted Lipid Metabolism and Inflammatory Response by Maintaining Endoplasmic Reticulum Homeostasis in Fish.
Impaired unfolded protein response, BDNF and synuclein markers in postmortem dorsolateral prefrontal cortex and caudate nucleus of patients with depression and Parkinson's disease.
Metabolic Rewiring in the Face of Genomic Assault: Integrating DNA Damage Response and Cellular Metabolism.
Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.
Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.
Expanding our understanding of synucleinopathies: proteinopathy, proteinopenia, and lipidopathy.
Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.
Mutation in α-Syn impairs insulin signaling pathway and induces neuroinflammation in the α-Syn Parkinson's Drosophila model.

Nucleic Acids Res. 2025 Feb 08. pii: gkaf088. [Epub ahead of print]53(4):

RNA exosome-driven RNA processing instructs the duration of the unfolded protein response.

Laura Matabishi-Bibi, Coralie Goncalves, Anna Babour.

Upon stresses, cellular compartments initiate adaptive programs meant to restore homeostasis. Dedicated to the resolution of transient perturbations, these pathways are typically maintained at a basal level, activated upon stress, and critically downregulated upon reestablishment of cellular homeostasis. As such, prolonged activation of the unfolded protein response (UPR), a conserved adaptive transcriptional response to defective endoplasmic reticulum (ER) proteostasis, leads to cell death. Here, we elucidate an unanticipated role for the nuclear RNA exosome, an evolutionarily conserved ribonuclease complex that processes multiple classes of RNAs, in the control of UPR duration. Remarkably, the inactivation of Rrp6, an exclusively nuclear catalytic subunit of the RNA exosome, curtails UPR signaling, which is sufficient to promote the cell's resistance to ER stress. Mechanistically, accumulation of unprocessed RNA species diverts the processing machinery that maturates the messenger RNA encoding the master UPR regulator Hac1, thus restricting the UPR. Significantly, Rrp6 expression is naturally dampened upon ER stress, thereby participating in homeostatic UPR deactivation.

DOI: https://doi.org/10.1093/nar/gkaf088
Biomolecules. 2025 Feb 08. pii: 248. [Epub ahead of print]15(2):

PERK-Olating Through Cancer: A Brew of Cellular Decisions.

Laurent Mazzolini, Christian Touriol.

  The type I protein kinase PERK is an endoplasmic reticulum (ER) transmembrane protein that plays a multifaceted role in cancer development and progression, influencing tumor growth, metastasis, and cellular stress responses. The activation of PERK represents one of the three signaling pathways induced during the unfolded protein response (UPR), which is triggered, in particular, in tumor cells that constitutively experience various intracellular and extracellular stresses that impair protein folding within the ER. PERK activation can lead to both pro-survival and proapoptotic outcomes, depending on the cellular context and the extent of ER stress. It helps the reprogramming of the gene expression in cancer cells, thereby ensuring survival in the face of oncogenic stress, such as replicative stress and DNA damage, and also microenvironmental challenges, including hypoxia, angiogenesis, and metastasis. Consequently, PERK contributes to tumor initiation, transformation, adaptation to the microenvironment, and chemoresistance. However, sustained PERK activation in cells can also impair cell proliferation and promote apoptotic death by various interconnected processes, including mitochondrial dysfunction, translational inhibition, the accumulation of various cellular stresses, and the specific induction of multifunctional proapoptotic factors, such as CHOP. The dual role of PERK in promoting both tumor progression and suppression makes it a complex target for therapeutic interventions. A comprehensive understanding of the intricacies of PERK pathway activation and their impact is essential for the development of effective therapeutic strategies, particularly in diseases like cancer, where the ER stress response is deregulated in most, if not all, of the solid and liquid tumors. This article provides an overview of the knowledge acquired from the study of animal models of cancer and tumor cell lines cultured in vitro on PERK's intracellular functions and their impact on cancer cells and their microenvironment, thus highlighting potential new therapeutic avenues that could target this protein.

Keywords:  ER stress; PERK; cancer; cell death; microenvironment; resistance; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/biom15020248
Nat Rev Nephrol. 2025 Feb 24.

Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease.

Jae Hyun Byun, Paul F Lebeau, Jackie Trink, Nikhil Uppal, Matthew B Lanktree, Joan C Krepinsky, Richard C Austin.

The endoplasmic reticulum (ER) has crucial roles in metabolically active cells, including protein translation, protein folding and quality control, lipid biosynthesis, and calcium homeostasis. Adverse metabolic conditions or pathogenic genetic variants that cause misfolding and accumulation of proteins within the ER of kidney cells initiate an injurious process known as ER stress that contributes to kidney disease and its cardiovascular complications. Initiation of ER stress activates the unfolded protein response (UPR), a cellular defence mechanism that functions to restore ER homeostasis. However, severe or chronic ER stress rewires the UPR to activate deleterious pathways that exacerbate inflammation, apoptosis and fibrosis, resulting in kidney injury. This insidious crosstalk between ER stress, UPR activation, oxidative stress and inflammation forms a vicious cycle that drives kidney disease and vascular damage. Furthermore, genetic variants that disrupt protein-folding mechanisms trigger ER stress, as evidenced in autosomal-dominant tubulointerstitial kidney disease and Fabry disease. Emerging therapeutic strategies that enhance protein-folding capacity and reduce the burden of ER stress have shown promising results in kidney diseases. Thus, integrating knowledge of how genetic variants cause protein misfolding and ER stress into clinical practice will enhance treatment strategies and potentially improve outcomes for various kidney diseases and their vascular complications.

DOI: https://doi.org/10.1038/s41581-025-00938-1
Curr Neuropharmacol. 2025 Feb 24.

ISR Modulators in Neurological Diseases.

Alexander Pavlovich Kalinin, Ekaterina Sergeevna Zubkova, Mikhail Yuryevich Menshikov, Yelena Victorovna Parfyonova.

  The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.

Keywords:  ATF4; Alzheimer's disease; Integrated stress response; Parkinson's disease; amyotrophic lateral sclerosis; eIF2; prion; traumatic brain injury.

DOI:  https://doi.org/10.2174/011570159X361653250213114821
Methods Mol Biol. 2025 ;2882 221-234

An In Vitro System to Study Mammalian GCN2 Regulation.

Glenn R Masson, Vanesa Vinciauskaite.

  General control non-derepressible 2 (GCN2) is an eIF2α kinase responsible for eliciting the integrated stress response (ISR) under amino acid starvation conditions. How GCN2 can sense amino acid starvation and become active in mammalian systems is not fully understood as there are a plethora of protein cofactors and post-translational modifications which may facilitate this transition. In this chapter, we describe the purification of recombinantly expressed human GCN2 from an insect cell expression system, and two assays which can quantify its kinase activity. Firstly, we describe an Western blot assay which can be used to directly assess phosphorylation of a downstream target, eIF2α. Secondly, we describe a luciferase-coupled kinase assay using an arginine-serine repeat peptide of eIF2α as the substrate. Together, these assays allow for the determination of GCN2 activity under a variety of conditions.

Keywords:  ADP-GLO; GCN2; eIF2α

DOI:  https://doi.org/10.1007/978-1-0716-4284-9_11
bioRxiv. 2025 Feb 12. pii: 2025.02.10.637566. [Epub ahead of print]

Protein degradation and growth dependent dilution substantially shape mammalian proteomes.

Andrew Leduc, Nikolai Slavov.

Cellular protein concentrations are maintained through a balance of synthesis and clearance. Clearance occurs through both protein degradation and growth-dependent dilution. At slow growth, clearance is dominated by degradation, which leads to the accumulation of long lived proteins. At fast growth, however, it is dominated by dilution, preventing this accumulation. Thus, the concentration of long lived proteins will be reduced unless cells compensate by preferentially increasing synthesis rates. To determine the dominant regulatory mechanisms, we quantified the degree of compensation between activated and resting human B cells and across mouse tissues. The results indicate that growth-dependent dilution is insufficiently compensated for by changes in protein synthesis, and it accounts for over a third of the concentration changes between high and low growth conditions. Furthermore, we find that about 25 % of the differences in protein concentration across all tissues are controlled by protein clearance. When comparing only slowly growing tissues such as the brain and pancreas, clearance differences explain as much as 42 %. Within a tissue or cell type, clearance variation is sufficient to account for 50 % of the abundance variation for all measured proteins at slow growth, contrasted with 7 % at fast growth. Thus, our model unifies previous observations with our new results and highlights a context-dependent and larger than previously appreciated contribution of protein degradation in shaping protein variation both across the proteome and across cell states.

DOI: https://doi.org/10.1101/2025.02.10.637566
J Mol Biol. 2025 Feb 22. pii: S0022-2836(25)00101-9. [Epub ahead of print] 169035

Lysosomal degradation of ER client proteins by ER-phagy and related pathways.

Carla Salomo-Coll, Natalia Jimenez-Moreno, Simon Wilkinson.

The endoplasmic reticulum (ER) is a major site of cellular protein synthesis. Degradation of overabundant, misfolded, aggregating or unwanted proteins is required to maintain proteostasis and avoid the deleterious consequences of aberrant protein accumulation, at a cellular and organismal level. While extensive research has shown an important role for proteasomally-mediated, ER-associated degradation (ERAD) in maintaining proteostasis, it is becoming clear that there is a substantial role for lysosomal degradation of "client" proteins from the ER lumen or membrane (ER-to-lysosome degradation, ERLAD). Here we provide a brief overview of the broad categories of ERLAD - predominantly ER-phagy (ER autophagy) pathways and related processes. We collate the client proteins known to date, either individual species or categories of proteins. Where known, we summarise the molecular mechanisms by which they are selected for degradation, and the setting in which lysosomal degradation of the client(s) is important for correct cell or tissue function. Finally, we highlight the questions that remain open in this area.

DOI: https://doi.org/10.1016/j.jmb.2025.169035
Antioxidants (Basel). 2025 Jan 22. pii: 125. [Epub ahead of print]14(2):

Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.

Szilvia Kiraly, Jack Stanley, Emily R Eden.

  The perception of lysosomes and mitochondria as entirely separate and independent entities that degrade material and produce ATP, respectively, has been challenged in recent years as not only more complex roles for both organelles, but also an unanticipated level of interdependence are being uncovered. Coupled lysosome and mitochondrial function and dysfunction involve complex crosstalk between the two organelles which goes beyond mitochondrial quality control and lysosome-mediated clearance of damaged mitochondria through mitophagy. Our understanding of crosstalk between these two essential metabolic organelles has been transformed by major advances in the field of membrane contact sites biology. We now know that membrane contact sites between lysosomes and mitochondria play central roles in inter-organelle communication. This importance of mitochondria-lysosome contacts (MLCs) in cellular homeostasis, evinced by the growing number of diseases that have been associated with their dysregulation, is starting to be appreciated. How MLCs are regulated and how their coordination with other pathways of lysosome-mitochondria crosstalk is achieved are the subjects of ongoing scrutiny, but this review explores the current understanding of the complex crosstalk governing the function of the two organelles and its impact on cellular stress and disease.

Keywords:  crosstalk; lysosomes; membrane contact sites; mitochondria

DOI:  https://doi.org/10.3390/antiox14020125
Pathogens. 2025 Feb 02. pii: 132. [Epub ahead of print]14(2):

Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus.

Yumi Jang, Fred Bunz.

  The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1α-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1α and XBP1. IRE1α was activated in response to HAdV5, but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1α activation. The de-repression of IRE1α following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by co-opting IRE1α and suppressing XBP1s. Our findings illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.

Keywords:  XBP1 splicing; adenovirus; p53; unfolded protein response

DOI:  https://doi.org/10.3390/pathogens14020132
Biomolecules. 2025 Feb 12. pii: 271. [Epub ahead of print]15(2):

TIM8 Deficiency in Yeast Induces Endoplasmic Reticulum Stress and Shortens the Chronological Lifespan.

Dong Tang, Wenbin Guan, Xiaodi Yang, Zhongqin Li, Wei Zhao, Xinguang Liu.

  Yeast TIM8 was initially identified as a homolog of human TIMM8A/DDP1, which is associated with human deafness-dystonia syndrome. Tim8p is located in the mitochondrial intermembrane space and forms a hetero-oligomeric complex with Tim13p to facilitate protein transport through the TIM22 translocation system. Previous research has indicated that TIM8 is not essential for yeast survival but does affect the import of Tim23p in the absence of the Tim8-Tim13 complex. Previous research on TIM8 has focused mainly on its involvement in the mitochondrial protein transport pathway, and the precise biological function of TIM8 remains incompletely understood. In this study, we provide the first report that yeast TIM8 is associated with the endoplasmic reticulum (ER) stress response and chronological senescence. We found that deletion of TIM8 leads to both oxidative stress and ER stress in yeast cells while increasing resistance to the ER stress inducer tunicamycin (TM), which is accompanied by an enhanced basic unfolded protein response (UPR). More importantly, TIM8 deficiency can lead to a shortened chronological lifespan (CLS) but does not affect the replicative lifespan (RLS). Moreover, we found that improving the antioxidant capacity further increased TM resistance in the tim8Δ strain. Importantly, we provide evidence that the knockdown of TIMM8A in ARPE-19 human retinal pigment epithelium cells can also induce ER stress, suggesting the potential function of the TIM8 gene in ER stress is conserved from budding yeast to higher eukaryotes. In summary, these results suggest novel roles for TIM8 in maintaining ER homeostasis and CLS maintenance.

Keywords:  CLS; ER stress; TIM8; oxidative stress; yeast

DOI:  https://doi.org/10.3390/biom15020271
Chem Biol Interact. 2025 Feb 25. pii: S0009-2797(25)00078-X. [Epub ahead of print] 111448

Endoplasmic reticulum stress inhibition preserves mitochondrial function and cell survival during the early onset of isoniazid-induced oxidative stress.

Truong Thi My Nhung, Nguyen Ky Phat, Trinh Tam Anh, Tran Diem Nghi, Nguyen Quang Thu, Ara Lee, Nguyen Tran Nam Tien, Nguyen Ky Anh, Huy Truong Nguyen, Kimoon Kim, Duc Ninh Nguyen, Dong Hyun Kim, Sang Ki Park, Nguyen Phuoc Long.

  A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. In this study, we used multi-omics profiling in vitro to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Additional analysis using transcriptomics data from repeated time-course INH treatments on human-specific hepatic microtissues revealed that cellular responses to ER stress and oxidative stress happened prior to disturbances in mitochondrial complexes. Mechanistic validation studies using time-lapse measurements of cytosolic and mitochondrial reactive oxygen species (ROS) revealed that INH initially triggered cytosolic ROS increasement and Nrf2 signaling pathway activation before mitochondrial ROS accumulation. Molecular imaging showed that INH subsequently disrupted mitochondrial function by impairing respiratory complexes I-IV and caused mitochondrial membrane proton leakage without affecting mitochondrial complex V, leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. Our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We also revealed the critical role of Nrf2 signaling in protecting hepatocytes under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming through regulating antioxidant gene expression and cellular lipid abundance. Alternative antioxidant pathways, including selenocompound metabolism, HIF-1 signaling, and the pentose phosphate pathway-also responded to INH-induced oxidative stress. Collectively, our study emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction that underlie INH-induced hepatotoxicity.

Keywords:  complex I-IV impairment; endoplasmic reticulum stress; isoniazid; mitochondria dysfunction; multi-omics; oxidative stress

DOI:  https://doi.org/10.1016/j.cbi.2025.111448
Int J Mol Sci. 2025 Feb 11. pii: 1525. [Epub ahead of print]26(4):

Small Heat Shock Proteins: Protein Aggregation Amelioration and Neuro- and Age-Protective Roles.

Tahani H Albinhassan, Bothina Mohammed Alharbi, Entissar S AlSuhaibani, Sameer Mohammad, Shuja Shafi Malik.

  Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging.

Keywords:  aging; amyloid fibrils; neurodegenerative disorders; protein aggregation; protein-folding; proteome; proteostasis; small heat shock proteins

DOI:  https://doi.org/10.3390/ijms26041525
Cells. 2025 Feb 13. pii: 270. [Epub ahead of print]14(4):

In Vitro Inhibition of Endoplasmic Reticulum Stress: A Promising Therapeutic Strategy for Patients with Crohn's Disease.

Bruno Lima Rodrigues, Lívia Bitencourt Pascoal, Lívia Moreira Genaro, Leonardo Saint Clair Assad Warrak, Beatriz Alves Guerra Rodrigues, Andressa Coope, Michel Gardere Camargo, Priscilla de Sene Portel Oliveira, Maria de Lourdes Setsuko Ayrizono, Lício Augusto Velloso, Raquel Franco Leal.

   BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease marked by an abnormal immune response and excessive pro-inflammatory cytokines, leading to impaired protein processing and endoplasmic reticulum (ER) stress. This stress, caused by the accumulation of misfolded proteins, triggers the unfolded protein response (UPR) through IRE1/Xbp-1, PERK/eIF2α, and ATF6 pathways, which are linked to intestinal inflammation. This study aimed to investigate ER stress in CD patients' intestinal mucosa and evaluate phenylbutyrate (PBA) as an ER stress inhibitor.
METHODS: Colon biopsies from CD patients and controls were cultured under five conditions, including 4-PBA treatments. Real-time PCR, cytokine level, and immunohistochemistry were performed.
RESULTS: Immunohistochemistry revealed that ER stress was activated in CD patients' intestinal epithelial cells and lamina propria cells. PERK/eIF2α, but not IRE1/Xbp-1 or ATF6, was upregulated in CD patients compared to controls. UPR-related genes (STC2, CALR, HSPA5, HSP90B1) were also elevated in CD patients. PBA treatment significantly reduced ER stress and UPR markers while decreasing apoptotic markers like DDIT3. Pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17, TNF- α, and sCD40L, were significantly reduced after PBA treatment.
CONCLUSION: ER stress and UPR pathways are activated in CD colonic mucosa, and PBA reduces these markers, suggesting potential therapeutic benefits for CD-related inflammation.

Keywords:  Crohn’s disease; endoplasmic reticulum stress; unfolded protein response

DOI:  https://doi.org/10.3390/cells14040270
bioRxiv. 2025 Feb 13. pii: 2025.02.10.637516. [Epub ahead of print]

Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.

Shiqi Diao, Jia Yi Zou, Shuo Wang, Nour Ghaddar, Jason E Chan, Hyungdong Kim, Nicolas Poulain, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.

The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.

DOI: https://doi.org/10.1101/2025.02.10.637516
Nat Commun. 2025 Feb 26. 16(1): 1982

Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.

Ge Gao, Yong Shi, Han-Xiang Deng, Dimitri Krainc.

Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.

DOI: https://doi.org/10.1038/s41467-025-57142-9
J Agric Food Chem. 2025 Feb 23.

HSF1 Mediates Palmitic Acid-Disrupted Lipid Metabolism and Inflammatory Response by Maintaining Endoplasmic Reticulum Homeostasis in Fish.

Kun Jia, Peng Shi, Lei Zhang, Xiaojun Yan, Jilin Xu, Kai Liao.

  Fish oil (FO) is being progressively replaced by palm oil (PO), which is rich in palmitic acid (PA). However, our understanding of the effects of PA on fish and the underlying molecular mechanisms remains limited. Heat shock transcription factor 1 (HSF1) is a critical transcription factor involved in stress response, but whether it responds to the effects of PA in fish remains unknown. In this study, in vitro and in vivo experiments were combined to investigate the molecular mechanisms by which HSF1 responds to PA. Our results indicated that PA induced fat accumulation, inflammation, and activation of protein processing in the endoplasmic reticulum (PPER) in the PaL cells. Moreover, the nuclear translocation of HSF1 was significantly increased by PA. After HSF1 was disrupted using small molecules (HSF1A and KRIBB11) or through HSF1A knockout, the PA-induced fat accumulation and expression levels of key genes related to PPER, lipid metabolism, and inflammation were significantly altered. Additionally, the analysis of CUT&Tag sequencing and dual-luciferase reporter showed that HSF1 protein can directly bind to the promoters of genes involved in PPER, lipid metabolism, and inflammatory response, thereby activating their transcriptional activity, especially HSC70, HSP90α, and HSP90β. Eicosapentaenoic acid (EPA) supplementation significantly improved the survival rate and growth performance of juvenile silver pomfret and reduced PA-induced adverse effects by inhibiting the activation of HSF1 in the liver. This study proves that HSF1 protein may respond to PA-induced lipid metabolism disorder and inflammatory response by maintaining endoplasmic reticulum stability in fish. Furthermore, EPA supplementation effectively counteracts PA-induced adverse effects.

Keywords:  HSF1; PPER pathway; inflammation; lipid metabolism; palmitic acid; silver pomfret and zebrafish

DOI:  https://doi.org/10.1021/acs.jafc.4c09302
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Feb 25. pii: S0278-5846(25)00053-3. [Epub ahead of print] 111299

Impaired unfolded protein response, BDNF and synuclein markers in postmortem dorsolateral prefrontal cortex and caudate nucleus of patients with depression and Parkinson's disease.

Unai Sarriés-Serrano, Lluis Miquel-Rio, Noemí Santana, Verónica Paz, María Sancho-Alonso, Luis F Callado, J Javier Meana, Analia Bortolozzi.

  Major depressive disorder (MDD) is characterized by significant impairment in social, emotional, and cognitive functioning. Its precise pathophysiology remains poorly understood. Alterations in protein homeostasis and some misfolded proteins have been identified within the brains of patients diagnosed with neuropsychiatric disorders. In contrast to neurodegenerative processes such as Parkinson's disease (PD), where the accumulation of aggregated α-synuclein (α-Syn) protein is a primary cause of significant neuronal loss, altered proteostasis in MDD may result in loss-of-function effects by modifying synaptic neuroplasticity. Moreover, aberrant activation of endoplasmic reticulum (ER) pathways may intensify the pathological alterations due to altered proteostasis. In this study, dorsolateral prefrontal cortex (dlPFC) and caudate nucleus from MDD patients and non-psychiatric controls were used. Postmortem samples of same brain areas from PD patients (Braak 2-3 and 5-6) and controls were also included. Protein levels of ER and unfolded protein response (UPR), synucleins (α-, β- and γ-Syn), and brain-derived neurotrophic factor (BDNF) were measured by Western-Blot. Phospho-eIF2α/eIF2α ratio was increased in the dlPFC and caudate nucleus of MDD and PD patients compared to their respective controls. Brain area-dependent changes in BiP and GRP94 levels were also found. We further detected accumulation of immature BDNF precursors and opposite changes in α- and β-Syn levels in the dlPFC of MDD and PD patients compared to controls. Our findings suggest that alterations in proteostasis contribute to the pathophysiology of MDD, as previously described in PD. A deeper understanding of the pathways involved will identify other candidate proteins and new targets with therapeutic potential.

Keywords:  Depression; Endoplasmic reticulum; Parkinson's disease; Postmortem human prefrontal cortex and caudate nucleus; Proteostasis; Synucleins

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111299
Biomolecules. 2025 Jan 23. pii: 168. [Epub ahead of print]15(2):

Metabolic Rewiring in the Face of Genomic Assault: Integrating DNA Damage Response and Cellular Metabolism.

Wenjian Ma, Sa Zhou.

  The DNA damage response (DDR) and cellular metabolism exhibit a complex, bidirectional relationship crucial for maintaining genomic integrity. Studies across multiple organisms, from yeast to humans, have revealed how cells rewire their metabolism in response to DNA damage, supporting repair processes and cellular homeostasis. We discuss immediate metabolic shifts upon damage detection and long-term reprogramming for sustained genomic stability, highlighting key signaling pathways and participating molecules. Importantly, we examine how DNA repair processes can conversely induce metabolic changes and oxidative stress through specific mechanisms, including the histone H2A variant X (H2AX)/ataxia telangiectasia mutated (ATM)/NADPH oxidase 1 (Nox1) pathway and repair-specific ROS signatures. The review covers organelle-specific responses and metabolic adaptations associated with different DNA repair mechanisms, with a primary focus on human cells. We explore the implications of this DDR-metabolism crosstalk in cancer, aging, and neurodegenerative diseases, and discuss emerging therapeutic opportunities. By integrating recent findings, this review provides a comprehensive overview of the intricate interplay between DDR and cellular metabolism, offering new perspectives on cellular resilience and potential avenues for therapeutic intervention.

Keywords:  DNA damage response (DDR); DNA repair; ROS; cancer therapy; cellular metabolism; oxidative stress

DOI:  https://doi.org/10.3390/biom15020168
Autophagy. 2025 Feb 27.

Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.

Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Gary Shangguan, Joseph M Wider, Maik Hüttemann, Thomas H Sanderson.

  Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an in vitro model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.

Keywords:  Fission; LONP1; PRKN; fusion; mitophagy; neuron

DOI:  https://doi.org/10.1080/15548627.2025.2472586
bioRxiv. 2025 Feb 16. pii: 2025.02.12.637879. [Epub ahead of print]

Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.

Yeongho Kim, Jan Parolek, Christopher G Burd.

Within cellular membranes, sphingomyelin is associated with cholesterol and this complex facilitates homeostatic regulation of membrane viscosity. Acute cholesterol depletion increases the synthesis of very-long-chain (VLC) sphingomyelin, but a link between lipid sensing and sphingolipid synthesis is lacking. Using sphingolipid metabolic flux analysis, we observed that VLC-ceramide, the precursor to VLC complex sphingolipids that are produced in the Golgi apparatus, was rapidly consumed after cholesterol depletion, while synthesis of long-chain sphingolipids was unaffected. Sphingolipid trafficking assays showed that cholesterol depletion enhances VLC-Ceramide trafficking from the endoplasmic reticulum to the Golgi apparatus. Changes in the sizes of coatomer II ER exit sites were correlated with increased VLC-Ceramide trafficking and concomitant increase in sphingomyelin. Depletion of Sec16A, a component of the COPII network, abolished VLC-SM synthesis. This study reveals ER-to-Golgi trafficking of VLC-Ceramide as a key regulatory node in organelle membrane homeostasis pathways.
Summary: In cellular membranes, sphingomyelin is associated with cholesterol. Metabolic flux analysis of sphingolipid metabolism showed that synthesis rate of sphingomyelin, but not ceramide, was increased after depletion of cholesterol due increased rate of COPII-dependent ER-to-Golgi transport of ceramide.

DOI: https://doi.org/10.1101/2025.02.12.637879
FEBS J. 2025 Feb 25.

Expanding our understanding of synucleinopathies: proteinopathy, proteinopenia, and lipidopathy.

Manuel Flores-León, Tiago F Outeiro.

  A possible consequence of the process of protein aggregation in neurodegenerative diseases is the depletion of soluble protein species (proteinopenia), which may, at least in some cases, reduce protein function/activity. This concept, which is often overlooked, may play a role in synucleinopathies such as Parkinson's disease (PD), and dementia with Lewy bodies (DLB), where the protein α-synuclein (aSyn) is known to accumulate in insoluble inclusions. aSyn is at the crossroads between cellular proteostasis and lipidostasis networks and, therefore, we must be aware of the complexity we face when we try to understand the molecular basis of synucleinopathies. Importantly, aSyn and β-glucocerebrosidase (GCase), a sphingolipid hydrolase also strongly implicated in PD and DLB, are connected to lipid biology and to protein quality control function. Thus, changes in the normal relationship between these two proteins may shift the balance in the cell and lead to proteinopathy and/or proteinopenia, while also affecting lipidostasis of cells in the brain. Thus, pathological mechanisms that are a consequence of (a) loss-of-function, (b) gain-of-toxic function, and (c) alterations in lipidostasis need to be carefully analyzed and integrated in our study of the molecular underpinnings of neurodegenerative mechanisms. Here, we highlight implications of the depletion of the soluble form of aSyn, and of GCase, and discuss how state-of-the-art 'omics technologies' could be deployed to assist in the clinical assessment of synucleinopathies.

Keywords:  Parkinson's disease; alpha‐synuclein; lipids; protein aggregation; synucleinopathy; transcription

DOI:  https://doi.org/10.1111/febs.70011
Nat Commun. 2025 Feb 24. 16(1): 1910

Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.

Alzheimer’s Disease Neuroimaging Initiative

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.

DOI: https://doi.org/10.1038/s41467-025-57032-0
Exp Cell Res. 2025 Feb 20. pii: S0014-4827(25)00056-4. [Epub ahead of print] 114460

Mutation in α-Syn impairs insulin signaling pathway and induces neuroinflammation in the α-Syn Parkinson's Drosophila model.

Pooja Rai, Rakesh Kumar.

  Mutations in the alpha-synuclein (α-Syn) gene have been causally linked to familial Parkinson's disease (PD). PD is primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra region of the brain. Α-Syn plays a pivotal role in the formation of Lewy bodies (LB), serving as a prominent pathological marker in PD. Growing evidence has illuminated the involvement of the insulin signaling pathway dysfunction in various neurodegenerative models. This study set out to explore how α-Syn influences the insulin signaling pathway and the overall lifespan of fruit flies afflicted with Parkinson's disease. It has been established that the α-Syn gene affects mitochondrial function, with mutations leading to mitochondrial impairments and increased oxidative stress, which ultimately contributes to the death of dopaminergic neurons.The impairment of mitochondrial function disrupts metabolism and exerts an adverse influence on the insulin signaling pathway. Furthermore, the unfolded protein response of the endoplasmic reticulum (ER) are investigated and observed a decrease in the expression of PERK (Protein kinase R-like ER kinase) during ER stress. These findings confirmed the intricate interplay between the insulin signaling pathway and the activation of the "PERK-ER" stress pathway. However, the degeneration of neurons triggers a neuroinflammatory response, which are found to be mitigated by the improvement of insulin signaling and the "PERK-ER" stress-related pathway. This study's results shed light on the novel regulatory role of PERK within the insulin signaling pathway and suggest its potential as a therapeutic candidate for modulating neuroinflammation in the context of α-Syn -associated Parkinson's Disease pathology.

Keywords:  ER-stress; Inflammatory; Insulin; Insulin receptor; Relish; α-Syn

DOI:  https://doi.org/10.1016/j.yexcr.2025.114460