Single-cell decoding of human islet cell type-specific alterations in type 2 diabetes reveals converging genetic- and state-driven β-cell gene expression defects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Pancreatic islets maintain glucose homeostasis through coordinated action of their constituent endocrine and affiliate cell types are central to type 2 diabetes (T2D) genetics pathophysiology. Our understanding robust human islet type-specific alterations in T2D remains limited. Here, we report comprehensive single transcriptome profiling 245,878 cells from a 48-donor cohort spanning non-diabetic (ND), pre-diabetic (PD), states, identifying 14 distinct detected every donor each glycemic state. Cohort analysis reveals ∼25-30% loss functional beta mass vs. ND or PD donors resulting (1) reduced total numbers/proportions (2) reciprocal 'high function' gain senescent β-cell subpopulations. We identify β-cells 511 differentially expressed genes (DEGs), including new (66.5%) validated (e.g., FXYD2, SLC2A2, SYT1 ), significant neuronal transmission vitamin A metabolism pathway alterations. Importantly, demonstrate newly identified DEG roles viability and/or insulin secretion link 47 DEGs diabetes-relevant phenotypes knockout mice, implicating them as potential causal dysfunction genes. Additionally, nominate candidate therapeutic targets 27 for which genetic risk variants (GWAS SNPs) pathophysiology (T2D ND) exert concordant expression effects. provide this freely accessible atlas data exploration, analysis, hypothesis testing. Together, study provides genomic resources insights into dysfunction.

Language: Английский

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Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases

npj Metabolic Health and Disease, Journal Year: 2025, Volume and Issue: 3(1)

Published: Feb. 3, 2025

Language: Английский

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Decoding Ischemic Stroke: Perspectives on the Endoplasmic Reticulum, Mitochondria, and Their Crosstalk

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103622 - 103622

Published: March 1, 2025

Stroke is known for its high disability and mortality rates. Ischemic stroke (IS), the most prevalent form, imposes a considerable burden on affected individuals. Nevertheless, existing treatment modalities are hindered by limitations, including narrow therapeutic windows, substantial adverse effects, suboptimal neurological recovery. Clarifying pathological mechanism of IS prerequisite developing new strategies. In this context, functional disruption mitochondria, endoplasmic reticulum (ER), crosstalk mechanisms between them have garnered increasing attention their contributory roles in progression IS. Therefore, review provides comprehensive summary current pathomechanisms associated with involvement ER mitochondria IS, emphasising Ca2+ destabilization homeostasis, stress, oxidative disordered mitochondrial quality control, transfer. Additionally, article highlights interaction as well mitochondrial-ER contacts (MERCs) that structurally connect ER, aiming to provide ideas references research

Language: Английский

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Sex-dependent adaptations in heart mitochondria from transgenic mice overexpressing cytochrome b5 reductase-3

Mitochondrion, Journal Year: 2025, Volume and Issue: unknown, P. 102004 - 102004

Published: Jan. 1, 2025

Cytochrome b

Language: Английский

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Tissue-dependent mechanosensing by cells derived from human tumors

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Alterations of the extracellular matrix (ECM), including both mechanical (such as stiffening ECM) and chemical variation adhesion proteins deposition hyaluronic acid (HA)) changes, in malignant tissues have been shown to mediate tumor progression. To survey how cells from different tissue types respond various changes ECM mechanics composition, we measured physical characteristics (adherent area, shape, cell stiffness, speed) 25 cancer 5 non-tumorigenic lines on 7 substrate conditions. Our results indicate substantial heterogeneity within across response mechanosensitive chemosensitive ECM. The analysis also underscores role HA with some showing presence soft that are similar those observed stiff substrate. This pan-cancer investigation highlights importance tissue-type line specificity for inferences made based comparison between properties normal cells. Lastly, using unsupervised machine learning, identify phenotypic classes characterize plasticity, i.e. distribution feature values attainable, a particular type ECM-based

Language: Английский

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Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease

Antioxidants, Journal Year: 2025, Volume and Issue: 14(2), P. 125 - 125

Published: Jan. 22, 2025

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

Language: Английский

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Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Glaucoma polygenic risk scores (PRS) effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study the UK Biobank, we investigated whether plasma metabolites enhanced prediction if metabolomic signature of high-genetic existed. Logistic regression models incorporating 168 NMR-based into PRS-based assessments were developed, multiple comparison corrections applied. While weakly predicted (Area Under Curve=0.579), they offered modest improvement PRS-only-based (P=0.004). We identified associated top decile, elevated glycolysis-related metabolites—lactate (P=8.8E-12), pyruvate (P=1.9E-10), citrate (P=0.02)—linked reduced prevalence. These combined significantly modified PRS-glaucoma relationship (P interaction =0.011). Higher total metabolite levels within highest quartile corresponded lower prevalence (Odds Ratio vs. lowest =0.71, 95% Confidence Interval [CI]=0.64–0.80). As is foundational linking glycolysis tricarboxylic acid cycle metabolism ATP generation, pursued experimental validation for putative biomarker human-relevant Mus musculus model. Dietary mitigated intraocular pressure (P=0.002) optic nerve damage (P<0.0003) Lmx1b V265D mice. findings highlight protective role pyruvate-related against suggest potential avenues therapeutic intervention.

Language: Английский

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Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 195 - 195

Published: Jan. 28, 2025

Focal swellings of dendrites (“dendritic blebbing”) together with structural damage mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations generally thought to be caused by so-called “overactivation” N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that activation extrasynaptic NMDARs, specifically when forming a protein–protein complex TRPM4, drives these traits. In contrast, strong synaptic NMDARs fails induce cell despite evoking plateau-type calcium signals comparable those generated NMDAR/TRPM4 complex, indicating high intracellular levels per se not toxic neurons. Using confocal laser scanning microscopy transmission electron microscopy, show disrupting using recently discovered small-molecule TwinF interface inhibitor FP802 inhibits NMDA-induced neurotoxicity-associated dendritic blebbing ER. It prevents, at least in part, disruption ER–mitochondria contact sites. findings establish trigger for organelles associated They suggest addition inducing high-amplitude, signals, generates second signal required neurotoxicity (“two-hit hypothesis”). As organelles, particularly mitochondria, is common feature many human neurodegenerative diseases, including Alzheimer’s disease amyotrophic lateral sclerosis (ALS), inhibitors have potential provide neuroprotection across broad spectrum diseases.

Language: Английский

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MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle

Cells, Journal Year: 2025, Volume and Issue: 14(7), P. 482 - 482

Published: March 22, 2025

Mitochondria-ER contact sites (MERCS) are vital for mitochondrial dynamics, lipid exchange, Ca2+ homeostasis, and energy metabolism. We examined whether metabolism changes during the cell cycle depend on MERCS dynamics regulated by outer protein rho GTPase 1 (MIRO1). Wound healing was assessed in mice with fibroblast-specific deletion of MIRO1. Wild-type MIRO1-/- fibroblasts vascular smooth muscle cells were evaluated proliferation, progression, number MERCS, distance, composition throughout cycle. Restoration MIRO1 mutants used to test role domains; transients using biochemical, immunodetection, fluorescence techniques. increased G1/S compared G0, which accompanied a notable rise protein–protein interactions involving VDAC1 IP3R as well GRP75 proximity-ligation assays. Split-GFP ER/mitochondrial contacts 40 nm also increased. Mitochondrial concentration ([Ca2+]), membrane potential, ATP levels correlated formation deficiency blocked progression cell-cycle-dependent altered ER release uptake. lacking Ca2+-sensitive EF hands or transmembrane domain did not rescue proliferation MERCS. controls an increase increases [Ca2+], driving metabolic activity through its hands.

Language: Английский

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Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: unknown, P. 119954 - 119954

Published: April 1, 2025

Language: Английский

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