Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA

The EMBO Journal, Год журнала: 2023, Номер 42(11)

Опубликована: Март 14, 2023

Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of shapes, we show strong linear correlation between fragmentation increased fatty acid oxidation (FAO) rates. Forced elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced upon knockdown knockout augments FAO as evident from respirometry metabolic tracing. Remarkably, genetic induction phenocopies distinct cell type-specific biological functions enhanced FAO. These include stimulation gluconeogenesis hepatocytes, insulin secretion islet β-cells exposed to acids, survival FAO-dependent lymphoma subtypes. We find that increases long-chain not short-chain identifying carnitine O-palmitoyltransferase 1 (CPT1) downstream effector regulation Mechanistically, determined reduces malonyl-CoA inhibition CPT1, CPT1 sensitivity inhibition. Overall, these findings underscore physiologic role for mechanism whereby fuel preference capacity determined.

Язык: Английский

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Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability

Cell Metabolism, Год журнала: 2024, Номер 36(5), С. 1088 - 1104.e12

Опубликована: Март 5, 2024

Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, gluconeogenesis activating hepatic CPT-1 pyruvate flux in the fed state. Fasting should have marginalized role ACC, but LDKO mice maintained elevated TCA intermediates preserved glycemia during fasting. These were accompanied compensatory induction proteolysis amino supply gluconeogenesis, which was offset protein synthesis feeding. Such adaptations may be related to Nrf2 activity, induced correlated with fasting acids. The findings reveal roles malonyl-CoA provide insight into broader inhibition.

Язык: Английский

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Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk

Annual Review of Biophysics, Год журнала: 2024, Номер 53(1), С. 147 - 168

Опубликована: Янв. 2, 2024

Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling immune responses. They highly dynamic at different structural functional levels. have been shown constantly undergo fusion fission processes dynamically interact with other such as the endoplasmic reticulum, peroxisomes, lipid droplets. The field of mitochondrial dynamics has evolved hand in technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer dynamics. In this review, we discuss following levels: (

Язык: Английский

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Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth

Metabolism, Год журнала: 2024, Номер 154, С. 155811 - 155811

Опубликована: Фев. 2, 2024

Язык: Английский

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MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus

Cardiovascular Diabetology, Год журнала: 2024, Номер 23(1)

Опубликована: Март 14, 2024

Abstract Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by multifaceted pathogenesis and limited therapeutic options. While lactate, byproduct of glycolysis, known be significantly elevated type 2 diabetes, its specific role DCM remains uncertain. This study reveals an abnormal upregulation monocarboxylate transporter 4 (MCT4) on the plasma membrane cardiomyocytes leading excessive lactate efflux from these cells. The disruption transport homeostasis perturbs intracellular lactate-pyruvate balance cardiomyocytes, resulting oxidative stress inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased augments histone H4K12 lactylation macrophages, facilitating infiltration within microenvironment. In vivo experiments have demonstrated inhibiting MCT4 effectively alleviates pathological damage, reduces macrophage infiltration, enhances cardiac function mice. Furthermore, clinical prediction model has been established, demonstrating notable association between peripheral blood levels diastolic dysfunction individuals with diabetes. underscores potential as prognostic biomarker for DCM. Ultimately, highlight pivotal involvement dysregulation energy metabolism macrophage-mediated inflammation These insights offer novel perspectives pave way development targeted strategies against this debilitating condition.

Язык: Английский

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A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 28, 2024

Abstract In the liver, mitochondria are exposed to different concentrations of nutrients due their spatial positioning across periportal and pericentral axis. How sense integrate these signals respond maintain homeostasis is not known. Here, we combine intravital microscopy, proteomics, functional assessment investigate mitochondrial heterogeneity in context liver zonation. We find that morphologically functionally distinct; beta-oxidation elevated regions, while lipid synthesis predominant mitochondria. addition, comparative phosphoproteomics reveals spatially distinct patterns composition potential regulation via phosphorylation. Acute pharmacological modulation nutrient sensing through AMPK mTOR shifts phenotypes linking gradients lobule heterogeneity. This study highlights role protein phosphorylation structure, function, overall hepatic metabolic These findings have important implications for physiology disease.

Язык: Английский

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Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress

Molecular Cell, Год журнала: 2024, Номер 84(14), С. 2732 - 2746.e5

Опубликована: Июль 1, 2024

Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria stress. These HK1-rings constrict at contact sites with endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). prevent fission by displacing dynamin-related (Drp1) from factor (Mff) (Fis1). The disassembly restoration correlated fission. Mechanistically, identified lack ATP glucose-6-phosphate (G6P) promotes formation HK1-rings. Mutations affect showed rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight HK1 is an stress sensor regulates shape, connectivity, metabolic activity mitochondria. Thus, may function in energy-stress-related pathologies.

Язык: Английский

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Redox regulation of UPR signalling and mitochondrial ER contact sites

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Июнь 7, 2024

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing exchange of material information, modulating calcium homeostasis, redox signalling, lipid transfer regulation mitochondrial dynamics. MERCS dynamic structures that allow cells to respond changes intracellular environment under normal homeostatic conditions, while their assembly/disassembly affected pathophysiological conditions such as ageing disease. Disruption protein folding lumen can activate Unfolded Protein Response (UPR), promoting remodelling membranes formation. The UPR stress receptor kinases PERK IRE1, located at or close MERCS. signalling be adaptive maladaptive, depending on whether disruption transient sustained. Adaptive via increase import, metabolism dynamics, maladaptive result excessive import activation apoptotic pathways. Targeting assembly an attractive therapeutic approach for range age-related neurodegeneration sarcopenia. This review highlights emerging evidence related role orchestrating inter-organelle communication mitochondria, ultimately determination function fate.

Язык: Английский

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Functional multi-organelle units control inflammatory lipid metabolism of macrophages

Nature Cell Biology, Год журнала: 2024, Номер 26(8), С. 1261 - 1273

Опубликована: Июль 5, 2024

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when adapt pathways support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral imaging approach for the comprehensive mapping of six key and interactions. We use this analysis on macrophages, immune that undergo rapid switches upon sensing bacterial inflammatory stimuli. Our results identify lipid droplets (LDs) as primary responder organelle, which forms three- four-way interactions with other organelles. While clusters endoplasmic reticulum (ER) mitochondria (mitochondria-ER-LD unit) help supply fatty acids LD growth, additional recruitment peroxisomes (mitochondria-ER-peroxisome-LD supports acid efflux from LDs. Interference individual components units direct functional consequences mediator synthesis. Together, show macrophages form multi-organellar adaptation provide an experimental strategy organelle-metabolic signalling hubs.

Язык: Английский

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Lipid Droplet–Mitochondria Contacts in Health and Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 6878 - 6878

Опубликована: Июнь 22, 2024

The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining homeostasis. Lipid droplets (LDs), once considered inert storage depots neutral lipids, are now recognized as dynamic organelles critical in lipid energy regulation. Mitochondria, the powerhouses cell, play central role production, metabolic pathways, signaling. physical functional contacts between LDs mitochondria facilitate direct transfer primarily fatty acids, which mitochondrial β-oxidation, thus influencing homeostasis health. This review highlights recent advances understanding mechanisms governing LD-mitochondria interactions their regulation, drawing attention to proteins pathways that mediate these contacts. We discuss physiological relevance interactions, emphasizing within cells, how processes response demands stress conditions. Furthermore, we explore pathological implications dysregulated particularly context diseases such obesity, diabetes, non-alcoholic liver disease, potential links cardiovascular neurodegenerative diseases. Conclusively, this provides comprehensive overview current underscoring significance suggesting future research directions could unveil novel therapeutic targets degenerative

Язык: Английский

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