Targeting organ-specific mitochondrial dysfunction to improve biological aging

Pharmacology & Therapeutics, Год журнала: 2024, Номер 262, С. 108710 - 108710

Опубликована: Авг. 22, 2024

In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites key regulators programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, mitochondrial dysfunction pivotal factor progressive age-related decline cellular homeostasis organ function. The current review examines recent advances understanding interplay between organ-specific aging. Thereby, we dissect molecular mechanisms underlying impairment associated with deterioration exploring DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated patterns, biogenesis, turnover, dynamics. We also highlight emerging therapeutic preclinical clinical tests that supposed rejuvenate such as antioxidants, biogenesis stimulators, modulators turnover Furthermore, discuss potential benefits challenges use interventions, emphasizing need for approaches given unique characteristics different tissues. conclusion, this highlights addressing mitigate aging, focusing on skin, liver, lung, brain, skeletal muscle, well reproductive, immune, cardiovascular systems. Based comprehensive multifaceted roles mitochondria, innovative may be developed optimized biological promote healthy across diverse

Язык: Английский

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GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113739 - 113739

Опубликована: Фев. 1, 2024

Glucose uptake increases during B cell activation and antibody-secreting (ASC) differentiation, but conflicting findings prevent a clear metabolic profile at different stages of activation. Deletion the glucose transporter type 1 (GLUT1) gene in mature cells (GLUT1-cKO) results normal development, it reduces germinal center ASCs. GLUT1-cKO mice show decreased antigen-specific antibody titers after vaccination. In vitro, GLUT1-deficient impaired activation, whereas established plasmablasts abolish glycolysis, relying on mitochondrial activity fatty acids. Transcriptomics metabolomics reveal an altered anaplerotic balance Despite attempts to compensate for deprivation by increasing mass expression associated with tricarboxylic acid cycle, hexosamine synthesis, ASCs lack metabolites energy production respiration, limiting protein synthesis. We identify GLUT1 as critical player defining response humoral immunity.

Язык: Английский

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Regulation of the NLRP3 inflammasome by autophagy and mitophagy

Immunological Reviews, Год журнала: 2024, Номер unknown

Опубликована: Окт. 17, 2024

Summary The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives broad inflammatory response. primary initial mediators of this response are pro‐IL‐1β and pro‐IL‐18, both which in an inactive form. Formation activates caspase‐1, cleaves pro‐IL‐18 triggers formation gasdermin D pores. Gasdermin pores allow for secretion active IL‐1β IL‐18 initiating organism‐wide can be beneficial to host; however, if inappropriately activated it lead significant pathology. While components known, precise details assembly less well defined conflicting. Here, we discuss several proposed pathways inflammasome. We examine role subcellular localization reciprocal regulation autophagy. focus on roles mitochondria mitophagy activating regulating Finally, detail impact pathologic responses development manifestations pulmonary disease.

Язык: Английский

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Real-Time Exposure to 3D-Printing Emissions Elicits Metabolic and Pro-Inflammatory Responses in Human Airway Epithelial Cells

Toxics, Год журнала: 2024, Номер 12(1), С. 67 - 67

Опубликована: Янв. 13, 2024

Three-dimensional (3D) printer usage in household and school settings has raised health concerns regarding chemical particle emission exposures during operation. Although the composition of 3D emissions varies depending on materials, little is known about impact that from different filament types may have respiratory underlying cellular mechanisms. In this study, we used an vitro exposure chamber system to deliver two popular 3D-printing types, acrylonitrile butadiene styrene (ABS) polylactic acid (PLA), directly human small airway epithelial cells (SAEC) cultured air–liquid interface Using a scanning mobility sizer (SMPS) optical (OPS), monitored particulate matter (PM) terms their size distribution, concentrations, calculated deposited doses. Elemental ABS PLA was assessed using electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM-EDX). Finally, compared effects cell viability, inflammation, metabolism SAEC. Our results reveal that, although filaments emitted higher total concentration particles smaller particles, SAEC were exposed similar doses for each type. Conversely, had distinct elemental compositions, which likely responsible differential oxidative stress, release inflammatory mediators, changes metabolism. Specifically, while ABS- PLA-emitted both reduced viability glutathione levels SAEC, significantly greater effect relative emissions. Additionally, pro-inflammatory cytokines including IL-1β, MMP-9, RANTES increased due exposure. While IL-6 IL-8 stimulated scenarios, VEGF exclusively exposures. Notably, induced metabolic perturbation amino acids metabolism, as well redox-regulated pathways arginine, methionine, cysteine, vitamin B3 whereas caused fatty carnitine dysregulation. Taken together, these advance our mechanistic understanding 3D-printer-emissions-induced toxicity highlight role properties play mediating outcomes.

Язык: Английский

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Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases

Autoimmunity Reviews, Год журнала: 2024, Номер 23(6), С. 103583 - 103583

Опубликована: Июнь 1, 2024

T cells are key drivers of the pathogenesis autoimmune diseases by producing cytokines, stimulating generation autoantibodies, and mediating tissue cell damage. Distinct mitochondrial metabolic pathways govern direction T-cell differentiation function rely on specific nutrients enzymes. Metabolic substrate uptake metabolism form foundational elements for activation, proliferation, differentiation, effector function, contributing to dynamic interplay between immunological signals in coordinating adaptive immunity. Perturbations availability enzyme activity may impair immunosuppressive fostering autoreactive responses disrupting immune homeostasis, ultimately disease pathogenesis. A growing body studies has explored how processes regulate diverse subsets such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), hepatitis (AIH), inflammatory bowel (IBD), psoriasis. This review describes coordination biology metabolism, including electron transport chain (ETC), oxidative phosphorylation, amino acid fatty one‑carbon metabolism. study elucidated intricate crosstalk programs, signal transduction pathways, transcription factors. summarizes potential therapeutic targets signaling diseases, providing insights future studies.

Язык: Английский

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THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108252 - 108252

Опубликована: Фев. 1, 2025

Every cell in the body is exposed to a certain level of CO2 and O2. Hypercapnia hypoxia elicit stress signals influence cellular metabolism function. Both conditions exert profound yet distinct effects on metabolic pathways mitochondrial dynamics, highlighting need for cells adapt changes gaseous microenvironment. The interplay between hypercapnia signalling key dictating homeostasis as microenvironmental O2 levels are inextricably linked. Hypercapnia, characterized by elevated pCO₂, introduces adaptations within aerobic pathways, affecting TCA cycle flux, lipid, amino acid metabolism, OXPHOS ETC. Hypoxia, defined reduced oxygen availability, necessitates shift from anaerobic glycolysis sustain ATP production, process orchestrated stabilisation HIF-1α. Given that present both physiological cancerous microenvironments, how might coexistence function niches tumor microenvironment?

Язык: Английский

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Triclosan-Mediated Metabolic Oxidative Stress-Triggered Cytoskeletal Alterations in Zebrafish Gills and Intestine: An Integrated Biomolecular and NMR-Based Metabolomics Study

Journal of Hazardous Materials, Год журнала: 2025, Номер unknown, С. 138251 - 138251

Опубликована: Апрель 1, 2025

Язык: Английский

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Mitochondria – the CEO of the cell

Journal of Cell Science, Год журнала: 2025, Номер 138(9)

Опубликована: Май 1, 2025

As we have learned more about mitochondria over the past decades, including their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at whim of cell. Rather, dynamic information energy processors play crucial directing dozens processes behaviors. They provide instructions to enact programs regulate various operations, such as complex metabolic networks, signaling innate immunity, even control cell fate, dictating when cells should divide, differentiate or die. To help current future generations biologists incorporate dynamic, multifaceted nature assimilate modern discoveries into scientific framework, need a 21st century 'rebranding'. In this Opinion article, argue be considered 'Chief Executive Organelle' - CEO

Язык: Английский

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Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Окт. 6, 2023

Abstract Pancreatic ductal adenocarcinoma (PDAC) cells have a great demand for nutrients in the form of sugars, amino acids, and lipids. Particularly, acids are critical cancer growth and, as intermediates, connect glucose, lipid nucleotide metabolism. PDAC meet these requirements by upregulating selective acid transporters. Here we show that SLC38A5 (SN2/SNAT5), neutral transporter is highly upregulated functional cells. Using CRISPR/Cas9-mediated knockout SLC38A5, its tumor promoting role an vitro cell line model well subcutaneous xenograft mouse model. metabolomics RNA sequencing, significant reduction many substrates OXPHOS inactivation response to deletion. Experimental validation demonstrates inhibition mTORC1, glycolysis mitochondrial respiration KO cells, suggesting serious metabolic crisis associated with Since activators mTORC1 TCA cycle intermediates/precursors, speculate insufficiency possible link between deletion respiration, underlying mechanism attenuation. Overall, promotes PDAC, thereby identifying novel, hitherto unknown, therapeutic target PDAC.

Язык: Английский

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Metabolic reprogramming of immune cells by mitochondrial division inhibitor-1 to prevent post-vascular injury neointimal hyperplasia

Atherosclerosis, Год журнала: 2024, Номер 390, С. 117450 - 117450

Опубликована: Янв. 13, 2024

New treatments are needed to prevent neointimal hyperplasia that contributes post-angioplasty and stent restenosis in patients with coronary artery disease (CAD) peripheral arterial (PAD). We investigated whether modulating mitochondrial function using division inhibitor-1 (Mdivi-1) could reduce post-vascular injury by metabolic reprogramming of macrophages from a pro-inflammatory anti-inflammatory phenotype.

Язык: Английский

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