bims-cemest 2025-02-02 papers

bims-cemest

Biomed News

on Cell metabolism and stress

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

PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
Lipid-Modulated, Graduated Inhibition of N-Glycosylation Pathway Priming Suggests Wide Tolerance of ER Proteostasis to Stress.
The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
Melatonin Ameliorates Organellar Calcium Homeostasis, Improving Endoplasmic Reticulum Stress-Mediated Apoptosis in the Vastus Lateralis Muscle of Both Sexes of Obese Diabetic Rats.
Dehydroamino acids and their crosslinks in Alzheimer's disease aggregates.
The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients.
Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.
Monoaminergic neurotransmitters are bimodal effectors of tau aggregation.
Mitochondria-Associated Endoplasmic Reticulum Membranes in Microglia: One Contact Site to Rule Them all.
Common alterations to astrocytes across neurodegenerative disorders.
Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation.
Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.
The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
Posttranslational modifications in cardiac metabolic remodeling mediated by metabolites: Implications for disease pathology and therapeutic potential.
Transcriptomic signatures and network-based methods uncover new senescent cell anti-apoptotic pathways and senolytics.
SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Elife. 2025 Jan 29. pii: RP102852. [Epub ahead of print]13

PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.

Ling Cheng, Ian Meliala, Yidi Kong, Jingyuan Chen, Christopher G Proud, Mikael Björklund.

  Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.

Keywords:  PEBP1; cell biology; human; integrated stress response; mitochondrial dysfunction

DOI:  https://doi.org/10.7554/eLife.102852
ACS Cent Sci. 2025 Jan 22. 11(1): 107-115

Lipid-Modulated, Graduated Inhibition of N-Glycosylation Pathway Priming Suggests Wide Tolerance of ER Proteostasis to Stress.

Andrew M Giltrap, Niamh Morris, Yin Yao Dong, Stephen A Cochrane, Thomas Krulle, Steven Hoekman, Martin Semmelroth, Carina Wollnik, Timea Palmai-Pallag, Elisabeth P Carpenter, Jonathan Hollick, Alastair Parkes, York Rudhard, Benjamin G Davis.

Protein N-glycosylation is a cotranslational modification that takes place in the endoplasmic reticulum (ER). Disruption of this process can result in accumulation of misfolded proteins, known as ER stress. In response, the unfolded protein response (UPR) restores proteostasis or responds by controlling cellular fate, including increased expression of activating transcription factor 4 (ATF4) that can lead to apoptosis. The ability to control and manipulate such a stress pathway could find use in relevant therapeutic areas, such as in treating cancerous states in which the native ER stress response is often already perturbed. The first committed step in the N-glycosylation pathway is therefore a target for potential ER stress modulation. Here, using structure-based design, the scaffold of the natural product tunicamycin allows construction of a panel capable of graduated inhibition of DPAGT1 through lipid-substituent-modulated interaction. The development of a quantitative, high-content, cellular immunofluorescence assay allowed precise determination of downstream mechanistic consequences (through the nuclear localization of key proxy transcription factor ATF4 as a readout of resulting ER stress). Only the most potent inhibition of DPAGT1 generates an ER stress response. This suggests that even low-level "background" biosynthetic flux toward protein glycosylation is sufficient to prevent response to ER stress. "Tuned" inhibitors of DPAGT1 also now seemingly successfully decouple protein glycosylation from apoptotic response to ER stress, thereby potentially allowing access to cellular states that operate at the extremes of normal ER stress.

DOI: https://doi.org/10.1021/acscentsci.4c01506
Nat Commun. 2025 Jan 25. 16(1): 1021

The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.

Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.

The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.

DOI: https://doi.org/10.1038/s41467-025-56346-3
Antioxidants (Basel). 2024 Dec 26. pii: 16. [Epub ahead of print]14(1):

Melatonin Ameliorates Organellar Calcium Homeostasis, Improving Endoplasmic Reticulum Stress-Mediated Apoptosis in the Vastus Lateralis Muscle of Both Sexes of Obese Diabetic Rats.

Diego Salagre, Miguel Navarro-Alarcón, Luis Gerardo González, Mohamed A Elrayess, Marina Villalón-Mir, Rocío Haro-López, Ahmad Agil.

  Endoplasmic reticulum (ER) stress is a crucial factor in the progression of obesity-related type 2 diabetes (diabesity), contributing to skeletal muscle (SKM) dysfunction, calcium imbalance, metabolic inflexibility, and muscle atrophy. The ER and mitochondria together regulate intracellular calcium levels, and melatonin, a natural compound with antioxidant properties, may alleviate these challenges. Our previous research showed that melatonin raises intracellular calcium and preserves muscle structure by enhancing mitochondrial function in obese diabetic rats. This study further explores melatonin's potential to reduce ER stress in the vastus lateralis (VL) muscle by modulating the unfolded protein response (UPR) and restoring calcium levels disrupted by diabesity. Five-week-old Zücker diabetic fatty (ZDF) rats and lean littermates of both sexes were divided into control and melatonin-treated groups (10 mg/kg/day for 12 weeks). Flame atomic absorption spectrometry results showed that melatonin restored VL intraorganellar calcium homeostasis, increasing calcium levels in mitochondria and reducing them in the ER by raising the activity and expression of calcium transporters in both sexes of ZDF rats. Melatonin also decreased ER stress markers (GRP78, ATF6, IRE1α, and PERK) and reduced pro-apoptosis markers (Bax, Bak, P-JNK, cleaved caspase 3 and 9) while increasing Bcl2 levels and melatonin receptor 2 (MT2) expression. These findings suggest that melatonin may protect against muscle atrophy in obese and diabetic conditions by mitigating ER stress and calcium imbalance, highlighting its therapeutic potential.

Keywords:  apoptosis; endoplasmic reticulum stress; melatonin; obesity; organellar calcium; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.3390/antiox14010016
Brain Commun. 2025 ;7(1): fcaf019

Dehydroamino acids and their crosslinks in Alzheimer's disease aggregates.

Samuel W Markovich, Brian L Frey, Mark Scalf, Michael R Shortreed, Lloyd M Smith.

  Alzheimer's disease (AD) is characterized by the accumulation of protein aggregates, which are thought to be influenced by posttranslational modifications (PTMs). Dehydroamino acids (DHAAs) are rarely observed PTMs that contain an electrophilic alkene capable of forming protein-protein crosslinks, which may lead to protein aggregation. We report here the discovery of DHAAs in the protein aggregates from AD, constituting an unknown and previously unsuspected source of extensive proteomic complexity. We used mass spectrometry-based proteomics to discover 404 sites of DHAA formation in 171 proteins from protein aggregate-enriched human brain samples, 6-fold more sites than observed in the soluble protein fractions. The DHAA modifications are observed both directly and in the form of conjugates after reacting with abundant cellular nucleophiles or crosslinking to nucleophilic amino acid residues. We report 11 such crosslinks, including three in the Tau protein, which are 10-fold more abundant in AD samples compared with age-matched controls. Many of the proteins found to contain DHAAs and their conjugates are involved in protein aggregation or pathways dysregulated in AD. DHAAs are prevalent modifications in the AD brain proteome and give rise to protein crosslinks that may contribute to protein aggregation.

Keywords:  Tau; myelin; neurofibrillary tangles; posttranslational modification; protein aggregation

DOI:  https://doi.org/10.1093/braincomms/fcaf019
J Biomed Sci. 2025 Jan 22. 32(1): 11

The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients.

Alina-Veronica Ghionescu, Mihaela Uta, Andrei Sorop, Catalin Lazar, Petruta R Flintoaca-Alexandru, Gabriela Chiritoiu, Livia Sima, Stefana-Maria Petrescu, Simona Olimpia Dima, Norica Branza-Nichita.

   BACKGROUND: Chronic hepatitis B virus (HBV) infection is a major risk for development of hepatocellular carcinoma (HCC), a frequent malignancy with a poor survival rate. HBV infection results in significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling, a contributing factor to carcinogenesis. As part of the UPR, the ER-associated degradation (ERAD) pathway is responsible for removing the burden of misfolded secretory proteins, to re-establish cellular homeostasis. Emerging evidence indicates consistent upregulation of ERAD factors, including members of the ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family in infection and various tumor types. However, the significance of this gene expression pattern in HBV-driven pathology is just beginning to be deciphered.
METHODS: In this study we quantified the expression of the ERAD factor EDEM3, in a cohort of HCC patients with and without HBV infection, and validated our results by analysis of publically available transcriptomic and microarray data sets. We performed mechanistic studies in HepaRG cells with modulated EDEM3 expression to address UPR, ERAD, autophagy and apoptosis signaling, and their consequences on HBV infection.
RESULTS: Our work revealed significantly elevated EDEM3 expression in HCC tissues irrespective of HBV infection, while the highest levels were observed in tissues from HBV-infected patients. Investigation of published transcriptomic data sets confirmed EDEM3 upregulation in independent HCC patient cohorts, associated with tumor progression, poor survival prognosis and resistance to therapy. EDEM3-overexpressing hepatic cells exhibited attenuated UPR and activated secretory autophagy, which promoted HBV production. Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death.
CONCLUSIONS: We provide evidence of major implications of the ERAD pathway in HBV infection and HCC development and progression. Our results suggest that ERAD activation in HBV-infected cells is a protective mechanism against prolonged ER stress, potentially contributing to establishment of chronic HBV infection and promoting tumorigenesis. Developing specific inhibitors for ERAD factors may be an attractive approach to improve efficiency of current antiviral and anticancer therapies.

Keywords:  Autophagy; Cancer; ER degradation; HBV infection

DOI:  https://doi.org/10.1186/s12929-024-01103-9
Mol Biol Cell. 2025 Jan 29. mbcE24110512

Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.

Alicia R Lane, Shatabdi Bhattacharjee, Stephanie A Zlatic, Anne M Roberts, Avanti Gokhale, Kaela S Singleton, Duc M Duong, Noah E Scher, Blaine R Roberts, Erica Werner, Victor Faundez.

Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that produced a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling of Atp7aflx/Y:: Vil1Cre/+ mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments in Drosophila demonstrated that copper deficiency dendritic phenotypes in class IV neurons are improved or rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency.

DOI: https://doi.org/10.1091/mbc.E24-11-0512
Sci Adv. 2025 Jan 31. 11(5): eadr8055

Monoaminergic neurotransmitters are bimodal effectors of tau aggregation.

Xinmin Chang, Amanda M Tse, Marina Fayzullina, Angela Albanese, Minchan Kim, Conner F Wang, Zipeng Zheng, Ruchira V Joshi, Christopher K Williams, Shino D Magaki, Harry V Vinters, Jeremy O Jones, Ian S Haworth, Paul M Seidler.

Neurotransmitters (NTs) mediate trans-synaptic signaling, and disturbances in their levels are linked to aging and brain disorders. Here, we ascribe an additional function for NTs in mediating intracellular protein aggregation by interaction with cytosolic protein fibrils. Cell-based seeding experiments revealed monoaminergic NTs as inhibitors of tau. Seeding is a disease-relevant mechanism involving catalysis by fibrils, leading to the aggregation of proteins in Alzheimer's disease and other neurodegenerative diseases. Chemotyping small molecules with varied backbone structures revealed determinants of aggregation inhibitors and catalysts. Among those identified were monoaminergic NTs. Dose titrations revealed bimodal effects indicative of fibril disaggregation, with aggregation catalysis occurring at low ratios of NTs and inhibited seeding ensuing at higher concentrations. Bimodal effects by NTs extend from in vitro systems to dopaminergic neurons, suggesting that pharmacotherapies that modify intracellular NT levels could shape the neuronal protein aggregation environment.

DOI: https://doi.org/10.1126/sciadv.adr8055
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564241312807

Mitochondria-Associated Endoplasmic Reticulum Membranes in Microglia: One Contact Site to Rule Them all.

Elisa Navarro, Jorge Montesinos.

  Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining tissue homeostasis by monitoring and responding to environmental changes through processes such as phagocytosis, cytokine production or synapse remodeling. Their dynamic nature and diverse functions are supported by the regulation of multiple metabolic pathways, enabling microglia to efficiently adapt to fluctuating signals. A key aspect of this regulation occurs at mitochondria-associated ER membranes (MAM), specialized contact sites between the ER and mitochondria. These structures facilitate the exchange of calcium, lipids, and metabolites and serve as metabolic and signaling hubs. This review synthesizes current research on how MAM influence microglial physiology, with an emphasis on their role in immunometabolism, offering new insights into the integration of metabolic and immune functions in the CNS and its impact in the context of neurodegeneration.

Keywords:  ER-mitochondria contact sites; inflammation; metabolism; microglia; mitochondria-associated ER membranes (MAM); neurodegeneration

DOI:  https://doi.org/10.1177/25152564241312807
Curr Opin Neurobiol. 2025 Jan 28. pii: S0959-4388(25)00001-7. [Epub ahead of print]90 102970

Common alterations to astrocytes across neurodegenerative disorders.

Aksinya Derevyanko, Tao Tao, Nicola J Allen.

  Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.

Keywords:  Astrocyte; Neurodegeneration; Neuroinflammation; Pathology

DOI:  https://doi.org/10.1016/j.conb.2025.102970
bioRxiv. 2025 Jan 13. pii: 2025.01.08.631231. [Epub ahead of print]

Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation.

Liam S Fitzgerald, Connor S Reynoso Spurrier, Nathan J Lau, Miles D Melamed, Lindsey A Burnett, Gretchen A Meyer, Chang Gui, Andrea L Hevener, James A Sanford, Simon Schenk.

Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial biogenesis, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximum uncoupled respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times (ZT), ZT 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.

DOI: https://doi.org/10.1101/2025.01.08.631231
Int J Mol Sci. 2025 Jan 09. pii: 498. [Epub ahead of print]26(2):

Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.

José J Serrano, Miguel Ángel Medina.

  The importance of redox systems as fundamental elements in biology is now widely recognized across diverse fields, from ecology to cellular biology. Their connection to metabolism is particularly significant, as it plays a critical role in energy regulation and distribution within organisms. Over recent decades, metabolism has emerged as a relevant focus in studies of biological regulation, especially following its recognition as a hallmark of cancer. This shift has broadened cancer research beyond strictly genetic perspectives. The interaction between metabolism and redox systems in carcinogenesis involves the regulation of essential metabolic pathways, such as glycolysis and the Krebs cycle, as well as the involvement of redox-active components like specific amino acids and cofactors. The feedback mechanisms linking redox systems and metabolism in cancer highlight the development of redox patterns that enhance the flexibility and adaptability of tumor processes, influencing larger-scale biological phenomena such as circadian rhythms and epigenetics.

Keywords:  cancer; emergence; feedback; metabolism; redox; reprogramming

DOI:  https://doi.org/10.3390/ijms26020498
Int J Mol Sci. 2024 Dec 26. pii: 92. [Epub ahead of print]26(1):

The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.

Amer Ahmed, Giorgia Natalia Iaconisi, Daria Di Molfetta, Vincenzo Coppola, Antonello Caponio, Ansu Singh, Aasia Bibi, Loredana Capobianco, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.

  Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.

Keywords:  cancer; metabolic reprogramming; metabolism; mitochondria; mitochondrial carriers

DOI:  https://doi.org/10.3390/ijms26010092
Metabolism. 2025 Jan 24. pii: S0026-0495(25)00013-7. [Epub ahead of print] 156144

Posttranslational modifications in cardiac metabolic remodeling mediated by metabolites: Implications for disease pathology and therapeutic potential.

Lifei Guo, Yuting Du, Heng Li, Ting He, Li Yao, Guodong Yang, Xuekang Yang.

  The nonenergy-producing or biomass-accumulating functions of metabolism are attracting increasing attention, as metabolic changes are gaining importance as discrete signaling pathways in modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.

Keywords:  Butyrylation; Cardiac disease; Crotonylation; Lactylation; Malonylation; Metabolites; O-GlcNAcylation; Palmitoylation; Posttranslational modification; Propionylation; Succinylation; β-Hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.metabol.2025.156144
FEBS J. 2025 Jan 27.

Transcriptomic signatures and network-based methods uncover new senescent cell anti-apoptotic pathways and senolytics.

Samael Olascoaga, Mina Konigsberg, Jesús Espinal-Enríquez, Hugo Tovar, Félix Matadamas-Martínez, Jaime Pérez-Villanueva, Norma Edith López-Diazguerrero.

  Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.

Keywords:  SCAPs; aging; senescence; senolytics; survival networks

DOI:  https://doi.org/10.1111/febs.17402
Nat Commun. 2025 Jan 24. 16(1): 978

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Izabella A Pena, Jeffrey S Shi, Sarah M Chang, Jason Yang, Samuel Block, Charles H Adelmann, Heather R Keys, Preston Ge, Shveta Bathla, Isabella H Witham, Grzegorz Sienski, Angus C Nairn, David M Sabatini, Caroline A Lewis, Nora Kory, Matthew G Vander Heiden, Myriam Heiman.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.

DOI: https://doi.org/10.1038/s41467-025-56130-3