bims-cemest 2025-01-05 papers

bims-cemest

Biomed News

on Cell metabolism and stress

Issue of 2025–01–05
thirteen papers selected by
Jessica Rosarda, Uniformed Services University

Basic Science and Pathogenesis.
Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss.
OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.
Revisiting the Benefits of Exercise for Alzheimer's Disease through the Lens of Ferroptosis: A New Perspective.
Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.
Berberine alleviates AGEs-induced ferroptosis by activating NRF2 in the skin of diabetic mice.
The Warburg Effect: Is it Always an Enemy?
Stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) sequesters misfolded proteins during stress.
The known unknowns of the Hsp90 chaperone.
Important Role of Mitochondrial Dysfunction in Immune Triggering and Inflammatory Response in Rheumatoid Arthritis.
Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors.
Hidden route of protein damage through oxygen-confined photooxidation.
Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.

Alzheimers Dement. 2024 Dec;20 Suppl 1 e087688

Basic Science and Pathogenesis.

Sara Bermudez, Junghyun Choi, Sunghoon Kim, Jacob W Vogel, Niaz Mahmood, Vivian Yuchan Zhu, Moein L Yaqubi, Jo Anne Stratton, Oskar Hansson, Argel Aguilar Valles, Luke M Healy, Nahum Sonenberg.

BACKGROUND: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022). mTOR complex 1 (mTORC1) inhibits the translation repressors, eukaryotic translation Initiation Factor 4E (eIF4E)-Binding Proteins (4E-BPs), via phosphorylation, which causes their release from eIF4E to promote mRNA translation (Hay and Sonenberg, 2004). mTORC1 promotes mitochondrial biogenesis via inhibition of 4E-BPs, by preferentially stimulating the translation of mitochondria-related mRNAs (Gandin et al., 2016; Morita et al., 2013). We investigated the mechanisms at the intersection of 4E-BP-dependent translational regulation and metabolism in microglial response to soluble Aβ.
METHOD: We carried out immunoblot analysis to investigate the phosphorylation status of 4E-BP1, the isoform most abundant in microglia, following exposure to Ab. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E-BPs, to alleviate translation suppression in microglia in vitro and in vivo. We crossed the microglia-specific 4E-BPs knockout mouse with a RiboTag mouse to pull-down ribosome-bound mRNAs, providing a genome-wide pool of actively translating mRNAs in the absence or presence of 4E-BPs. Finally, we examined the relationship between 4E-BP1 levels and neuroinflammation markers in cerebrospinal fluid (CSF) of AD patients.
RESULT: We showed that 4E-BP1 is inhibited acutely upon exposure to soluble Ab, which is dependent on Spleen Tyrosine Kinase (SYK) activation upstream of mTORC1, but is reduced upon chronic exposure. Furthermore, 4E-BP1 expression is induced during prolonged exposure to Ab. The deletion of 4E-BPs in microglia in vitro leads to an increase in mitochondrial mass and reliance on oxidative phosphorylation while decreasing expression of pro-inflammatory mediators and cell death upon exposure to Ab. We observed that increased levels of 4E-BP1 in the CSF of patients with Aβ pathology are associated with higher neurodegeneration (Nfl) in the presence of microglial activation.
CONCLUSION: We demonstrate that mTORC1 signaling critically impacts microglia physiology and promotes neuroprotective functions via 4E-BP1 inhibition. 4E-BP1 activity in microglia engenders a dysfunctional or detrimental state that may lead to increased neurodegeneration. Therefore, 4E-BP1 is an attractive target for microglia modulation in AD.

DOI: https://doi.org/10.1002/alz.087688
Front Mol Neurosci. 2024 ;17 1443401

Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss.

Guanzhen Li, Huiming Yang, Peiyuan Zhang, Yan Guo, Lili Yuan, Shujiao Xu, Yingxue Yuan, Huabao Xiong, Haiyan Yin.

  Sensorineural hearing loss (SNHL) is characterized by a compromised cochlear perception of sound waves. Major risk factors for SNHL include genetic mutations, exposure to noise, ototoxic medications, and the aging process. Previous research has demonstrated that inflammation, oxidative stress, apoptosis, and autophagy, which are detrimental to inner ear cells, contribute to the pathogenesis of SNHL; however, the precise mechanisms remain inadequately understood. The endoplasmic reticulum (ER) plays a key role in various cellular processes, including protein synthesis, folding, lipid synthesis, cellular calcium and redox homeostasis, and its homeostatic balance is essential to maintain normal cellular function. Accumulation of unfolded or misfolded proteins in the ER leads to endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) signaling pathway. The adaptive UPR has the potential to reestablish protein homeostasis, whereas the maladaptive UPR, associated with inflammation, oxidative stress, apoptosis, and autophagy, can lead to cellular damage and death. Recent evidence increasingly supports the notion that ERS-mediated cellular damage responses play a crucial role in the initiation and progression of various SNHLs. This article reviews the research advancements on ERS in SNHL, with the aim of elucidating molecular biological mechanisms underlying ERS in SNHL and providing novel insights for the treatment.

Keywords:  apoptosis; autophagy; endoplasmic reticulum stress; inflammation; oxidative stress; sensorineural hearing loss; unfolded protein response

DOI:  https://doi.org/10.3389/fnmol.2024.1443401
Nat Commun. 2025 Jan 02. 16(1): 300

OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.

Alessandra Donato, Fiona K Ritchie, Lachlan Lu, Mehershad Wadia, Ramon Martinez-Marmol, Eva Kaulich, Kornraviya Sankorrakul, Hang Lu, Sean Coakley, Elizabeth J Coulson, Massimo A Hilliard.

Oxidative stress, caused by the accumulation of reactive oxygen species (ROS), is a pathological factor in several incurable neurodegenerative conditions as well as in stroke. However, our knowledge of the genetic elements that can be manipulated to protect neurons from oxidative stress-induced cell death is still very limited. Here, using Caenorhabditis elegans as a model system, combined with the optogenetic tool KillerRed to spatially and temporally control ROS generation, we identify a previously uncharacterized gene, oxidative stress protective 1 (osp-1), that protects C. elegans neurons from oxidative damage. Using rodent and human cell cultures, we also show that the protective effect of OSP-1 extends to mammalian cells. Moreover, we demonstrate that OSP-1 functions in a strictly cell-autonomous fashion, and that it localizes to the endoplasmic reticulum (ER) where it has an ER-remodeling function. Finally, we present evidence suggesting that OSP-1 may exert its neuroprotective function by influencing autophagy. Our results point to a potential role of OSP-1 in modulating autophagy, and suggest that overactivation of this cellular process could contribute to neuronal death triggered by oxidative damage.

DOI: https://doi.org/10.1038/s41467-024-55105-0
Aging Dis. 2024 Dec 24.

Revisiting the Benefits of Exercise for Alzheimer's Disease through the Lens of Ferroptosis: A New Perspective.

Zikang Hao, Xinmeng Guo, Jiawen Wu, Guang Yang.

Ferroptosis, an iron-dependent form of programmed cell death driven by oxidative stress, plays a crucial role in the progression of Alzheimer's disease (AD). Aging diminishes antioxidant systems that maintain iron homeostasis, particularly affecting the glutathione peroxidase (GPX) system, leading to increased ferroptosis and exacerbated neurodegeneration and neuroinflammation in AD. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating genes involved in antioxidant defense and ferroptosis. In this review, we examine the interconnected roles of Nrf2 signaling, iron metabolism, and ferroptosis in AD, and discuss how regular physical exercise-known to enhance antioxidant capacity-might influence these processes. Despite evidence linking exercise to improved cognitive function in AD and its role in modulating oxidative stress, there is a paucity of research specifically addressing how exercise affects ferroptosis in the AD brain. To address this gap, we utilized bioinformatics techniques to identify potential pathways and mechanisms by which exercise may mitigate ferroptosis in AD through Nrf2 signaling. Analyzing gene expression profiles from the GEO database, we identified differentially expressed ferroptosis-related genes in the hippocampus following exercise intervention. Hub genes like SLC2A1, TXN, MEF2C, and KRAS were significantly upregulated, suggesting that exercise may activate a network enhancing antioxidant defenses and regulating iron metabolism via Nrf2. Our findings propose a novel mechanism whereby exercise alleviates abnormal ferroptosis in the AD brain through modulation of Nrf2 signaling. This study highlights the need for further research to validate these findings and explore exercise as a therapeutic strategy for AD by targeting ferroptosis.

DOI: https://doi.org/10.14336/AD.2024.1560
Sci Rep. 2024 Dec 28. 14(1): 31401

Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.

Ken Ohno, Hisashi Murakami, Naohisa Ogo, Akira Asai.

  The cell painting assay is useful for understanding cellular phenotypic changes and drug effects. To identify other aspects of well-known chemicals, we screened 258 compounds with the cell painting assay and focused on a mitochondrial punctate phenotype seen with disulfiram. To elucidate the reason for this punctate phenotype, we looked for clues by examining staining steps and gene knockdown as well as examining protein solubility and comparing cell lines. From these results, we found that the punctate phenotype was caused by protein insolubility in the mitochondrial matrix. Interestingly, the punctate phenotype of disulfiram was sensitive to the relative expression of LonP1, a protease in the mitochondrial matrix that regulates proteostasis, suggesting that the punctate phenotype manifests when the protein quality control capacity in the mitochondrial matrix is exceeded. Moreover, we discovered that disulfiram and its derivatives, which have all been reported to increase acetaldehyde in the blood after the in vivo intake of alcohol, induced a punctate phenotype as well. The investigated punctate phenotype not only provides a novel clue for elucidating the common mechanism of action among disulfiram derivatives but is also a novel example of chemical perturbation of proteostasis in the mitochondrial matrix.

Keywords:  Cell painting assay; Disulfiram; LonP1; Oligomycin A; Protein insolubility; Proteostasis

DOI:  https://doi.org/10.1038/s41598-024-82939-x
Exp Biol Med (Maywood). 2024 ;249 10280

Berberine alleviates AGEs-induced ferroptosis by activating NRF2 in the skin of diabetic mice.

Chunjie Jiang, Guojuan Lao, Jianmin Ran, Ping Zhu.

  Advanced glycation end products (AGEs) have adverse effects on the development of diabetic complications. Berberine (BBR), a natural alkaloid, has demonstrated its ability to promote the delayed healing of skin wounds. However, the impact of BBR on AGEs-induced ferroptosis in skin cells and the underlying molecular mechanisms remains unexplored. This study investigated the involvement of ferroptosis in AGEs-induced keratinocyte death, and the impact of BBR on ferroptosis in a db/db mouse model with long-term hyperglycemia was elucidated. A remarkable reduction in cell viability was observed along with increased malondialdehyde (MDA) production in AGEs-induced HaCaT cells. Intracellular reactive oxygen species (ROS) and iron levels were elevated in cells exposed to AGEs. Meanwhile, the protein expression of glutathione peroxidase 4 (GPX4) and ferritin light chain (FTL) was significantly decreased in AGEs-treated cells. However, pretreatment with BBR markedly protected cell viability and inhibited MDA levels, attenuating the intracellular ROS and iron levels and increased expression of GPX4 and FTL in vitro. Significantly diminished antiferroptotic effects of BBR on AGEs-treated keratinocytes were observed upon the knockdown of the nuclear factor E2-related factor 2 (NRF2) gene. In vivo, GPX4, FTL, and FTH expression in the epidermis of diabetic mice was significantly reduced, accompanied by enhanced lipid peroxidation. Treatment with BBR effectively rescued lipid peroxidation accumulation and upregulated GPX4, FTL, FTH, and NRF2 levels in diabetic skin. Collectively, the findings indicate that ferroptosis may play a significant role in AGEs-induced keratinocyte death. BBR protects diabetic keratinocytes against ferroptosis, partly by activating NRF2.

Keywords:  NRF2; advanced glycation end productions; berberine; ferroptosis; keratinocytes

DOI:  https://doi.org/10.3389/ebm.2024.10280
Front Biosci (Landmark Ed). 2024 Nov 27. 29(12): 402

The Warburg Effect: Is it Always an Enemy?

Christos Papaneophytou.

  The Warburg effect, also known as 'aerobic' glycolysis, describes the preference of cancer cells to favor glycolysis over oxidative phosphorylation for energy (adenosine triphosphate-ATP) production, despite having high amounts of oxygen and fully active mitochondria, a phenomenon first identified by Otto Warburg. This metabolic pathway is traditionally viewed as a hallmark of cancer, supporting rapid growth and proliferation by supplying energy and biosynthetic precursors. However, emerging research indicates that the Warburg effect is not just a strategy for cancer cells to proliferate at higher rates compared to normal cells; thus, it should not be considered an 'enemy' since it also plays complex roles in normal cellular functions and/or under stress conditions, prompting a reconsideration of its purely detrimental characterization. Moreover, this review highlights that distinguishing glycolysis as 'aerobic' and 'anaerobic' should not exist, as lactate is likely the final product of glycolysis, regardless of the presence of oxygen. Finally, this review explores the nuanced contributions of the Warburg effect beyond oncology, including its regulatory roles in various cellular environments and the potential effects on systemic physiological processes. By expanding our understanding of these mechanisms, we can uncover novel therapeutic strategies that target metabolic reprogramming, offering new avenues for treating cancer and other diseases characterized by metabolic dysregulation. This comprehensive reevaluation not only challenges traditional views but also enhances our understanding of cellular metabolism's adaptability and its implications in health and disease.

Keywords:  Warburg effect; cancer metabolism; cellular metabolism; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.31083/j.fbl2912402
FEBS J. 2024 Dec 30.

Stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) sequesters misfolded proteins during stress.

Benjamin S Rutledge, Young J Kim, Donovan W McDonald, Juan C Jurado-Coronel, Marco A M Prado, Jill L Johnson, Wing-Yiu Choy, Martin L Duennwald.

  Co-chaperones are key elements of cellular protein quality control. They cooperate with the major heat shock proteins Hsp70 and Hsp90 in folding proteins and preventing the toxic accumulation of misfolded proteins upon exposure to stress. Hsp90 interacts with the co-chaperone stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) and activator of Hsp90 ATPase protein 1 (Aha1) among many others. Sti1 and Aha1 control the ATPase activity of Hsp90, but Sti1 also facilitates the transfer of client proteins from Hsp70 to Hsp90, thus connecting these two major branches of protein quality control. We find that misbalanced expression of Sti1 and Aha1 in yeast and mammalian cells causes severe growth defects. Also, deletion of STI1 causes an accumulation of soluble misfolded ubiquitinated proteins and a strong activation of the heat shock response. We discover that, during proteostatic stress, Sti1 forms cytoplasmic inclusions in yeast and mammalian cells that overlap with misfolded proteins. Our work indicates a key role of Sti1 in proteostasis independent of its Hsp90 ATPase regulatory functions by sequestering misfolded proteins during stress.

Keywords:  Sti1; co‐chaperone; protein homeostasis; scaffolding; yeast

DOI:  https://doi.org/10.1111/febs.17389
Elife. 2024 Dec 31. pii: e102666. [Epub ahead of print]13

The known unknowns of the Hsp90 chaperone.

Laura-Marie Silbermann, Benjamin Vermeer, Sonja Schmid, Katarzyna Tych.

  Molecular chaperones are vital proteins that maintain protein homeostasis by assisting in protein folding, activation, degradation, and stress protection. Among them, heat-shock protein 90 (Hsp90) stands out as an essential proteostasis hub in eukaryotes, chaperoning hundreds of 'clients' (substrates). After decades of research, several 'known unknowns' about the molecular function of Hsp90 remain unanswered, hampering rational drug design for the treatment of cancers, neurodegenerative, and other diseases. We highlight three fundamental open questions, reviewing the current state of the field for each, and discuss new opportunities, including single-molecule technologies, to answer the known unknowns of the Hsp90 chaperone.

Keywords:  Hsp90; molecular biophysics; molecular chaperones; proteostasis; structural biology

DOI:  https://doi.org/10.7554/eLife.102666
J Inflamm Res. 2024 ;17 11631-11657

Important Role of Mitochondrial Dysfunction in Immune Triggering and Inflammatory Response in Rheumatoid Arthritis.

Pingshun Li, Mengru Zhou, Jia Wang, Jiexiang Tian, Lihuan Zhang, Yong Wei, Fang Yang, Yali Xu, Gang Wang.

  Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, primarily characterized by chronic symmetric synovial inflammation and erosive bone destruction.Mitochondria, the primary site of cellular energy production, play a crucial role in energy metabolism and possess homeostatic regulation capabilities. Mitochondrial function influences the differentiation, activation, and survival of both immune and non-immune cells involved in RA pathogenesis. If the organism experiences hypoxia, genetic predisposition, and oxidative stress, it leads to mitochondrial dysfunction, which further affects immune cell energy metabolism, synovial cell proliferation, apoptosis, and inflammatory signaling, causing the onset and progression of RA; and, mitochondrial regulation is becoming increasingly important in the treatment of RA.In this review, we examine the structure and function of mitochondria, analyze the potential causes of mitochondrial dysfunction in RA, and focus on the mechanisms by which mitochondrial dysfunction triggers chronic inflammation and immune disorders in RA. We also explore the effects of mitochondrial dysfunction on RA immune cells and osteoblasts, emphasizing its key role in the immune response and inflammatory processes in RA. Furthermore, we discuss potential biological processes that regulate mitochondrial homeostasis, which are of great importance for the prevention and treatment of RA.

Keywords:  immune triggers; inflammatory response; mitochondria; osteoblasts; rheumatoid arthritis; synovial cells

DOI:  https://doi.org/10.2147/JIR.S499473
Nat Commun. 2025 Jan 02. 16(1): 252

Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors.

Shashank Shekhar, Charles Tracy, Peter V Lidsky, Raul Andino, Katherine J Wert, Helmut Krämer.

Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2αS50 phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain.

DOI: https://doi.org/10.1038/s41467-024-55576-1
Nat Commun. 2024 Dec 30. 15(1): 10873

Hidden route of protein damage through oxygen-confined photooxidation.

Seoyoon Kim, Eojin Kim, Mingyu Park, Seong Ho Kim, Byung-Gyu Kim, Seungjin Na, Victor W Sadongo, W C Bhashini Wijesinghe, Yu-Gon Eom, Gwangsu Yoon, Hannah Jeong, Eunhye Hwang, Chaiheon Lee, Kyungjae Myung, Chae Un Kim, Jeong-Mo Choi, Seung Kyu Min, Tae-Hyuk Kwon, Duyoung Min.

Oxidative modifications can disrupt protein folds and functions, and are strongly associated with human aging and diseases. Conventional oxidation pathways typically involve the free diffusion of reactive oxygen species (ROS), which primarily attack the protein surface. Yet, it remains unclear whether and how internal protein folds capable of trapping oxygen (O2) contribute to oxidative damage. Here, we report a hidden pathway of protein damage, which we refer to as O2-confined photooxidation. In this process, O2 is captured in protein cavities and subsequently converted into multiple ROS, primarily mediated by tryptophan residues under blue light irradiation. The generated ROS then attack the protein interior through constrained diffusion, causing protein damage. The effects of this photooxidative reaction appear to be extensive, impacting a wide range of cellular proteins, as supported by whole-cell proteomic analysis. This photooxidative mechanism may represent a latent oxidation pathway in human tissues directly exposed to visible light, such as skin and eyes.

DOI: https://doi.org/10.1038/s41467-024-55168-z
Int J Med Sci. 2025 ;22(1): 188-196

Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.

Yang Shen, Xin Gao, Ying Xiang, Hao Zhou, Hang Zhu, Qiang Wu, Jinfeng Liu.

  This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific Fundc1 knockout (Fundc1CKO ) mice, we demonstrated that Fundc1 deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. Fundc1 deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.

Keywords:  ATF5; FUNDC1; mito-UPR; mitochondria.

DOI:  https://doi.org/10.7150/ijms.100523