An inter-organelle contact between endosomal GLP-1R, ER VAP-B, and the mitochondrial AKAP SPHKAP triggers PKA-dependent MIC19 phosphorylation and β-cell mitochondrial remodelling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 30, 2024

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing its turnover and improving quality control. While the GLP-1R is well known to stimulate cAMP production leading activation of Protein Kinase A (PKA) Exchange Activated cyclic AMP 2 (Epac2) signalling, there a lack understanding molecular mechanisms linking GLP-1RA-induced signalling with remodelling improved function. Here we present dataset that demonstrates that, following GLP-1RA stimulation in pancreatic β-cells, interacts endoplasmic reticulum (ER) membrane contact site (MCS) organising factor VAP-B from an endocytic location engage SPHKAP, A-kinase anchoring protein (AKAP) associated type diabetes (T2D) adiposity genome-wide association studies (GWAS), trigger pool mitochondrially localised PKA phosphorylates cristae organizing system (MICOS) complex component MIC19, enabling optimal β-cell

Язык: Английский

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Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Pathophysiology, Год журнала: 2025, Номер 32(1), С. 9 - 9

Опубликована: Фев. 13, 2025

Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate action, or combination of both. Mitochondrial dysfunction has emerged as significant contributor to the aetiology diabetes, affecting various processes critical for glucose homeostasis. This review aims elucidate complex link between mitochondrial and covering spectrum diabetes types, role mitochondria in resistance, highlighting pathophysiological mechanisms, DNA damage, altered biogenesis dynamics. Additionally, it discusses clinical implications complications its complications, diagnostic approaches assessing function diabetics, therapeutic strategies, future directions, research opportunities.

Язык: Английский

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TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

ABSTRACT Activation of innate immune signaling occurs during the progression immunometabolic diseases, including type 2 diabetes (T2D), yet impact on glucose homeostasis is controversial. Here, we report that E3 ubiquitin ligase TRAF6 integrates signals following diet-induced obesity to promote through induction mitophagy. Whereas was dispensable for and pancreatic β-cell function under basal conditions, pivotal insulin secretion, mitochondrial respiration, increases in mitophagy metabolic stress both mouse human islets. Indeed, critical recruitment machinery within ubiquitin-mediated (Parkin-dependent) receptor-mediated (Parkin-independent) pathways upon stress. Intriguingly, effect deficiency fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role cross-regulation ubiquitin- receptor- mediated restriction Parkin. Together, illustrate β-cells engage adaptively respond diabetogenic environment.

Язык: Английский

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Dietary bioactive compounds for type 2 diabetes: A comprehensive review of molecular interactions and mechanistic insights

Journal of Functional Foods, Год журнала: 2025, Номер 126, С. 106705 - 106705

Опубликована: Фев. 25, 2025

Язык: Английский

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Genome-Scale Metabolic Modeling of Human Pancreas with Focus on Type 2 Diabetes

OMICS A Journal of Integrative Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Type 2 diabetes (T2D) is characterized by relative insulin deficiency due to pancreatic beta cell dysfunction and resistance in different tissues. Not only cells but also other islet (alpha, delta, polypeptide [PP]) are critical for maintaining glucose homeostasis the body. In this overarching context given that a deeper understanding of T2D pathophysiology novel molecular targets much needed, studies integrate experimental computational biology approaches offer veritable prospects innovation. study, we report on single-cell RNA sequencing data integration with generic Human1 model generate context-specific genome-scale metabolic models alpha, beta, PP nondiabetic states and, importantly, at resolution. Moreover, flux balance analysis was performed investigation activities cells. By altering oxygen uptakes networks, documented ways which hypoglycemia, hyperglycemia, hypoxia led changes various cellular subsystems. Reporter metabolite revealed significant transcriptional around several metabolites involved sphingolipid keratan sulfate metabolism alpha cells, fatty acid myoinositol phosphate delta Taken together, leveraging modeling, research bridges gap between theory clinical practice, offering comprehensive framework advance our T2D, contributes new knowledge toward development targeted precision medicine interventions.

Язык: Английский

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Small Molecules and Epigenetic Modifiers in Facilitating Pancreatic β-cell Formation: A Comprehensive Insight

Advances in experimental medicine and biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus

Mitochondrion, Год журнала: 2025, Номер unknown, С. 102039 - 102039

Опубликована: Апрель 1, 2025

Язык: Английский

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Mitochondrial Health in Cardiometabolic Diseases and Aging: Clinical Applications of Therapeutic Fasting and Natural Supplements

IntechOpen eBooks, Год журнала: 2025, Номер unknown

Опубликована: Май 7, 2025

Mitochondria play a central role in cellular energy production, metabolic regulation, and oxidative stress management. Their dysfunction is hallmark of cardiometabolic diseases, including obesity, diabetes, metabolic-associated steatotic liver disease (MASLD), cardiovascular (CVD). Mitochondrial decline, characterized by impaired phosphorylation, excessive reactive oxygen species (ROS) mitochondrial DNA (mtDNA) mutations, also accelerates aging contributes to senescence dysregulation. This chapter explores the essential health diseases aging, focusing on emerging therapeutic strategies restore function. Therapeutic fasting, intermittent fasting caloric restriction, has shown significant potential enhance mitophagy, promote biogenesis, improve efficiency. Concurrently, natural supplements such as resveratrol, curcumin, spermidine, green tea polyphenols vitamins have demonstrated efficacy mitigating stress, preserving mtDNA integrity, supporting electron transport chain activity. highlights mechanisms addressing dysfunction, offering innovative approaches manage extend healthspan, combat aging-related disorders. The discusses challenges future directions for translating these findings into clinical practice.

Язык: Английский

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Melatonin Alleviates Oxidative Stress‐Induced Mitochondrial Dysfunction Through Ameliorating NAD⁺ Homeostasis of hDPSCs for Cell‐Based Therapy

Journal of Pineal Research, Год журнала: 2025, Номер 77(3)

Опубликована: Апрель 1, 2025

ABSTRACT Human dental pulp stem cells (hDPSCs) exhibit amazing therapeutic abilities in a variety of diseases due to their remarkable self‐renewal capacity and multi‐differentiation potential. However, potential could be weakened by various factors such as oxidative stress cell survival microenvironment In Vivo. Here, we explored the protective effect mechanism melatonin (Mel) on hDPSCs transplanted type 1 diabetes mellitus (T1DM) rat model. Nicotinamide adenine dinucleotide (NAD + ) metabolism mitochondrial function were remarkably impaired T1DM rats caused stress, while combination Mel post‐hDPSCs transplantation rebalance NAD homeostasis through regulating NAMPT‐NAD ‐SIRT1 axis. Furthermore, significantly reduced intracellular reactive oxygen species, alleviated senescence apoptosis exposed hydrogen peroxide ameliorating depletion dysfunction. The role extremely essential tissue engineering regenerative medicine.

Язык: Английский

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The Gut Microbial Metabolite Butyrate Alleviates IL‐1β‐Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets

The FASEB Journal, Год журнала: 2025, Номер 39(11)

Опубликована: Май 30, 2025

ABSTRACT Butyrate, a gut microbiota‐derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences function redox balance protect cells from interleukin‐1beta (IL‐1β)‐induced stress. Pancreatic mouse islets were treated with IL‐1β and/or for 10 days model chronic in type 2 diabetes, their effects on health studied. Butyrate protected against IL‐1β‐induced impairment of insulin secretion by enhancing as evidenced an increased glucose‐stimulated oxygen consumption rate higher membrane potential compared treatment alone. mass, but the mitochondria appeared smaller rounded, indicating fragmentation. contrast, co‐treatment promoted hyperfusion, elongated mitochondria, levels fusion proteins Opa1 Mfn2, lower fission protein Fis1 Furthermore, reduced reactive species (ROS) production, antioxidant enzyme gene expression, oxidation, protection further enhanced increasing glutathione (GSH) ratio GSH oxidized (GSSG). These findings suggest that acts potent modulator balance, counteracting dysfunction providing therapeutic strategy improving inflammatory conditions.

Язык: Английский

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