KAT6A acetylation drives metabolic adaptation to mediate cellular growth and mitochondrial metabolism through AMPK interaction

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

Published: Jan. 14, 2025

Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show KAT6A acetylation is crucial for mitochondrial function cell growth. Proteomic analysis revealed acetylated at (K)816 in hearts of mice fed under hypertension, which enhances its interaction AMPK regulatory subunits. RNA-sequencing acetylation-mimetic mutant stimulates signaling cardiomyocytes. Moreover, mitigated phenylephrine-induced dysfunction cardiomyocyte hypertrophy via activation. However, KAT6A-K816R acetylation-resistant knock-in unexpectedly exhibited smaller enhanced activity, conferring protection against neurohumoral stress-induced remodeling. These findings indicate regulates cellular growth by interacting modulating activity K816-acetylation type-specific manner.

Language: Английский

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Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential

Cells, Journal Year: 2025, Volume and Issue: 14(5), P. 324 - 324

Published: Feb. 20, 2025

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite advancement treatment options. Therefore, better understanding pathogenesis HF essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics pathological cardiac remodeling, contributing to HF. The mechanisms involved in development remodeling consequent multifactorial, this review, key underlying discussed. These have been divided into following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, oxidative stress; (ii) lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) (iv) impaired autophagy; (v) inflammatory responses; (vi) programmed cell death, apoptosis, pyroptosis, ferroptosis; (vii) endothelial dysfunction; (viii) contractility. Preclinical data suggest that there merit targeting identified pathways; however, their clinical implications outcomes regarding treating need further investigation future. Herein, we introduce molecular pivotal onset progression HF, as well compounds related potential preventing or rescuing This, therefore, offers an avenue design discovery therapies

Language: Английский

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Lipotoxicity as a therapeutic target in the type 2 diabetic heart

Journal of Molecular and Cellular Cardiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Evaluation of antiobesogenic properties of fermented foods: In silico insights

Journal of Food Science, Journal Year: 2025, Volume and Issue: 90(3)

Published: March 1, 2025

Obesity prevalence has steadily increased over the past decades. Standard approaches, such as energy expenditure, lifestyle changes, a balanced diet, and use of specific drugs, are conventional strategies for preventing or treating disease its associated complications. Fermented foods their subsequent bioactive constituents now believed to be novel strategy that can complement already existing approaches managing this disease. Recent developments in systems biology bioinformatics have made it possible model simulate compounds interactions. The adoption silico models contributed discovery fermented product targets helped testing hypotheses regarding mechanistic impact underlying functions food components. From studies explored, key findings suggest affect adipogenesis, lipid metabolism, appetite regulation, gut microbiota composition, insulin resistance, inflammation related obesity, which could lead new ways treat these conditions. These outcomes were linked probiotics, prebiotics, metabolites, complex substances produced during fermentation. Overall, show promise innovative tools obesity management by influencing metabolic pathways overall health.

Language: Английский

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Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging

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

Published: March 19, 2025

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to dispensable development and function in mice. However, the long-term consequences of downregulation remain unknown. Here we demonstrate that ketone catabolism is essential preserving cardiac during aging. expression succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme ketolysis, decreases with aging female SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal at 10 weeks age but progressively develop dysfunction remodeling as they age, without overt hypertrophy both sexes. Notably, supplementation via ketogenic diet partially rescues contractile cKO mice, suggesting oxidation-independent mechanisms contribute cardiomyopathy caused by downregulation. These findings indicate crucial maintaining aging, confer cardioprotection independently

Language: Английский

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Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via ERK/Drp1 pathway

Cardiovascular Diabetology, Journal Year: 2025, Volume and Issue: 24(1)

Published: March 20, 2025

Increasing evidence highlights the critical role of Piezo1 in cardiovascular diseases, with its expression upregulated diabetic heart. However, involvement pathogenesis cardiomyopathy (DCM) remains unclear. This study aims to elucidate regulatory mitochondrial dynamics within context DCM and investigate underlying mechanisms. We constructed cardiac-specific knockout (Piezo1∆Myh6) mice. Type 1 diabetes was induced using streptozotocin (STZ) injection while type 2 established through a high-fat diet combined STZ. Echocardiography assessed left ventricular function, histological evaluations used HE Masson staining examine cardiac pathology Piezo1fl/fl controls, Piezo1∆Myh6 Mitochondrial function including oxygen species level, morphology, respiration rate were also assessed. Our findings revealed that myocardium mice high-glucose-treated cells. Cardiac-specific improved dysfunction ameliorated fibrosis Moreover, deficiency attenuated impairment. exhibited increased calpain activity excessive fission mediated by Drp1 obvious reduced fusion; however, restored levels dysfunction. These observations corroborated H9C2 cells neonatal mouse cardiomyocytes. phosphorylation ERK1/2 vivo vitro. or treatment inhibitor function. provides first is elevated modulation dynamics, which reversed deficiency. Thus, inhibition may provide promising therapeutic strategy for DCM. In cardiomyocytes mice, Ca2+ entry upregulates activity, phosphorylated level Drp1. Therefore, shown hearts. Whereas, cardiomyocyte-specific alleviates

Language: Английский

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The Role of Ultra-Processed Foods in Inflammation and Aging

IntechOpen eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Processed foods are that undergo physical, chemical, or biological processes to enhance durability, extend shelf life, improve taste and texture, alter nutritional content, facilitate consumption. While traditional processed preserved packaged through methods such as canning salting, ultra-processed (UPFs) industrially produced formulations ready-to-eat ready-to-heat typically contain little no whole food ingredients. Recent evidence suggests the adverse health effects of UPFs may not only be due nutrients they provide but also non-nutritive components their impact on gut health. Diets rich in associated with cellular changes leading oxidative stress, which turn contributes inflammation aging processes. In this context, reducing consumption UPFs, limiting refined carbohydrates, modifying meal timing frequency recommended for improving

Language: Английский

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Quantifying Renal Lipid Accumulation in Obese Murine Models Using Magnetic Resonance Imaging (MRI)

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: unknown, P. 151765 - 151765

Published: April 1, 2025

Language: Английский

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Acetyltransferase in cardiovascular disease and aging

The Journal of Cardiovascular Aging, Journal Year: 2024, Volume and Issue: 4(4)

Published: Dec. 31, 2024

Acetyltransferases are enzymes that catalyze the transfer of an acetyl group to a substrate, modification referred as acetylation. Loss-of-function variants in genes encoding acetyltransferases can lead congenital disorders, often characterized by intellectual disability and heart muscle defects. Their activity is influenced dietary nutrients alter coenzyme A levels, key cofactor. Cardiovascular diseases, including ischemic, hypertensive, diabetic diseases - leading causes mortality elderly largely attributed prolonged lifespan growing prevalence metabolic syndrome. thus serve crucial link between lifestyle modifications, cardiometabolic disease, aging through both epigenomic non-epigenomic mechanisms. In this review, we discuss roles relevance acetyltransferases. While sirtuin family deacetylases has been extensively studied longevity, particularly fasting-mediated NAD+ metabolism, recent research brought attention essential health aging-related pathways, cell proliferation, DNA damage response, mitochondrial function, inflammation, senescence. We begin with overview acetyltransferases, classifying them domain structure, canonical non-canonical lysine N-terminal sialic acid O-acetyltransferases. then advances understanding acetyltransferase-related pathologies, focusing on cardiovascular disease aging, explore their potential therapeutic applications for promoting older individuals.

Language: Английский

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Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy

Metabolism, Journal Year: 2024, Volume and Issue: 162, P. 156062 - 156062

Published: Nov. 6, 2024

Language: Английский

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