Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome

JCI Insight, Год журнала: 2024, Номер 9(17)

Опубликована: Авг. 1, 2024

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding pore-forming inward rectifier Kir6.1 regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ channels (KATP). In this study, we investigated changes endothelium mice which -associated Kcnj8 or Abcc9 were knocked-in to endogenous loci. We found that endothelium-dependent dilation was impaired small mesenteric arteries from mice. Loss vasodilation led increased vasoconstriction response intraluminal pressure treatment with adrenergic agonist phenylephrine. also either KATP GOF acute activation pinacidil amplitude frequency wave-like Ca2+ events generated vasodilator carbachol. Increased cytosolic signaling activity arterial endothelial cells associated elevated mitochondrial [Ca2+] enhanced reactive oxygen species (ROS) peroxynitrite levels. Scavenging intracellular ROS restored mutations. conclude overload generation, subsequently leads nitric oxide consumption formation, cause dysfunction syndrome.

Язык: Английский

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Cannabidiol Prevents Heart Failure Dysfunction and Remodeling Through Preservation of Mitochondrial Function and Calcium Handling

JACC Basic to Translational Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Involvement of Oxidative Stress and Antioxidants in Modification of Cardiac Dysfunction Due to Ischemia–Reperfusion Injury

Antioxidants, Год журнала: 2025, Номер 14(3), С. 340 - 340

Опубликована: Март 14, 2025

Delayed reperfusion of the ischemic heart (I/R) is known to impair recovery cardiac function and produce a wide variety myocardial defects, including ultrastructural damage, metabolic alterations, subcellular Ca2+-handling abnormalities, activation proteases, changes in gene expression. Although I/R injury has been reported induce formation reactive oxygen species (ROS), inflammation, intracellular Ca2+ overload, generation oxidative stress considered play critical role development dysfunction. Increases production superoxide, hydroxyl radicals, oxidants, such as hydrogen peroxide hypochlorous acid, occur hearts subjected injury. In fact, mitochondria are major source excessive ROS due impairment electron transport system well xanthine oxidase NADPH oxidase. Nitric oxide synthase, mainly present endothelium, also activated injury, leading nitric oxide, which, upon combination with superoxide generates nitrosative stress. Alterations function, sarcolemma, sarcoplasmic reticulum activities, mitochondrial phosphorylation, protease simulated exposing oxyradical-generating (xanthine plus oxidase) or H2O2. On other hand, endogenous antioxidants dismutase, catalase, glutathione peroxidase, concentration transcription factor (Nrf2), which modulates expression various antioxidants, depressed hearts. Furthermore, pretreatment catalase N-acetylcysteine, mercaptopropionylglycerine observed attenuate I/R-induced handling Ca2+-regulatory activities; additionally, it found depress improve function. These observations indicate that intimately involved pathological effects different alterations Thus, we faced task developing safe effective agents for upregulating therapy

Язык: Английский

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Association between admission serum calcium levels and in‑hospital mortality in acute myocardial infarction patients with cardiovascular-kidney-metabolic syndrome

Endocrine, Год журнала: 2025, Номер unknown

Опубликована: Март 29, 2025

Acute myocardial infarction (AMI) with cardiovascular-kidney-metabolic (CKM) condition is linked to a high in-hospital mortality. Some previous studies reported that calcium may be related mortality among patients AMI. However, there no report about the association between serum and AMI CKM syndrome. Therefore, this study investigated admission levels in cohort of This retrospective enrolled 2537 admitted including 270 CKM. All data were extracted from electronic medical records May 2019 April 2024. According reference range calcium, all divided into two groups, low group (0-2.10 mmol/L) non-low (from 2.11 mmol/L). The primary endpoint was rate significantly higher (16.8%, n = 19) compared (8.3%, 13). After adjusting for age, gender, hypertension, atrial fibrillation, stroke smoke, demonstrated (OR 2.409, 95% CI: 1.105-5.249, p < 0.05). In subgroup analyses, multivariable logistic regression models indicated an independent predictor females 7.453; CI 1.751-31.730; 0.05) elderly 3.122; 1.167-8.348; after adjustments smoke. Restricted cubic splines (RCS) analysis showed dose-response relationship (nonlinear P value 0.067). Admission hypocalcemia risk factor syndrome, especially individuals (aged ≥76 years) females.

Язык: Английский

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Mechanism of MCUB‐Dependent Inhibition of Mitochondrial Calcium Uptake

Journal of Cellular Physiology, Год журнала: 2025, Номер 240(4)

Опубликована: Апрель 1, 2025

ABSTRACT Mitochondrial Ca 2+ levels are regulated to balance stimulating respiration against the harm of overload. Contributing this balance, main channel transporting into matrix, mitochondrial uniporter, can incorporate a dominant‐negative subunit (MCUB). MCUB is homologous pore‐forming MCU, but when present in pore‐lining tetramer, inhibits transport. Here, using cell lines deleted both MCU and MCUB, we identify three factors that contribute MCUB‐dependent inhibition. First, protein requires express. The effect mediated via N‐terminal domain (NTD) MCUB. Replacement NTD with recovers autonomous expression fails rescue uptake. Surprisingly, mutations affect interactions accessory subunits or conduction pore all failed uptake, suggesting mechanism inhibition may involve more global rearrangements. Second, concatemeric tetramers varying MCU:MCUB ratios, find incorporation does not abolish conduction, rather influx proportional amount channel. Reducing than abolishing transport consistent retaining highly‐conserved selectivity filter DIME sequence. Finally, apply live‐cell Förster resonance energy transfer establish endogenous stoichiometry 2:2 MCU:MCUB. Taken together, our results suggest preferentially incorporates nascent uniporters, linearly correlates degree transport, creating precise, tunable for cells regulate

Язык: Английский

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Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies—A Comprehensive Narrative Review

Genes, Год журнала: 2025, Номер 16(4), С. 465 - 465

Опубликована: Апрель 18, 2025

Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have associated condition, while female generally do not experience condition. There are several organs that may be affected, but striking cardiological involvement. Cardiovascular disease, which trigger starting diagnostic procedure in a proband, include range of diseases from severely dilated heart to hypertrophic spectrum anomalies encountered. Left ventricular non-compaction also occasionally This cardiac event reveal prognosis affected patients. In this narrative review, we highlight gene’s characteristics, reactome, features cardiovascular disease observed patients with BTHS, emphasize most current studies BTHS cardiomyopathy, and delineate biological underlying mechanisms supporting proposal new therapeutic options.

Язык: Английский

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Aminooxyacetic acid ameliorates alcohol-induced learning and memory deficits through BDNF-TrkB pathway and calcium homeostasis

European journal of medical research, Год журнала: 2025, Номер 30(1)

Опубликована: Май 5, 2025

Chronic alcohol-related brain damage (ARBD) is mainly manifested as learning and memory impairment cognitive decline in the long term. Ca2+ plays a key role impairment. The increase of intracellular concentration can directly cause mitochondrial dysfunction, destroy normal physiological signal transduction, accelerate process decline. Aminooxyacetic acid (AOAA), selective inhibitor Cystathionineβ-synthase (CBS), has good effect on variety diseases, including improving stroke reducing incidence convulsions. However, its potential maintaining functions by regulating functional status remains uncertain. In this study, chronic alcoholism rats human neuroblastoma cells (SHSY-5Y) were used research objects to establish model. We aimed elucidate specific mechanisms which AOAA protects alcohol-induced Through Morris water maze test, LTP Western blot (WB), immunohistochemistry (IHC), observation under electron microscope, calcium ion measurement membrane measurement, it was found that could not only regulate level endoplasmic reticulum stress (ERS) caused H2S elevation, but also maintain valve Sec61 channel restoring BIP, indicator ERS, significantly alleviate dysfunction overload, optimize function. mechanism may be closely related BDNF-TrkB pathway.

Язык: Английский

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Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake

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

Опубликована: Ноя. 26, 2024

ABSTRACT Mitochondrial Ca 2+ levels are regulated to balance stimulating respiration against the harm of overload. Contributing this balance, main channel transporting into matrix, mitochondrial uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous pore-forming MCU, but when present in pore-lining tetramer, inhibits transport. Here, using cell lines deleted both MCU and MCUB, we identify three factors that contribute MCUB-dependent inhibition. First, protein requires express. The effect mediated via N-terminal domain (NTD) MCUB. Replacement NTD with recovers autonomous expression fails rescue uptake. Surprisingly, mutations affect interactions accessory subunits or conduction pore all failed uptake, suggesting mechanism inhibition may involve global rearrangements. Second, concatemeric tetramers varying MCU:MCUB ratios, find incorporation does not abolish conduction, rather influx proportional amount channel. Reducing than abolishing transport consistent retaining highly-conserved selectivity filter DIME sequence. Finally, apply live-cell Förster resonance energy transfer establish endogenous stoichiometry 2:2 MCU:MCUB. Taken together, our results suggest preferentially incorporates nascent uniporters, linearly correlates degree transport, creating precise, tunable for cells regulate

Язык: Английский

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Protective Effects and Mechanisms of Inhibiting Endoplasmic Reticulum Stress on Cold Seawater Immersion Combined with Hemorrhagic Shock

Journal of Inflammation Research, Год журнала: 2024, Номер Volume 17, С. 4923 - 4940

Опубликована: Июль 1, 2024

Cold seawater immersion aggravates hemorrhagic shock-induced homeostasis imbalance and organ dysfunction, leading to increased mortality. Previous studies have shown that treatments targeting oxidative stress mitochondrial dysfunction limited efficacy for cold combined with shock (SIHS). Thus, the mechanisms responsible SIHS need further investigation.

Язык: Английский

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Causal gene identification using mitochondria-associated genome-wide mendelian randomization in atrial fibrillation

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Июль 29, 2024

Mitochondrial dysfunction is one of the important patho-mechanisms in development atrial fibrillation (AF) with underidentified genetic pathophysiology.

Язык: Английский

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