Lipid overload: trigger or consequence of mitochondrial oxidative stress in ventilator-induced diaphragmatic dysfunction?
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ABSTRACT:
SUBMITTER: Lecuona E
PROVIDER: S-EPMC3530207 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
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Lipid overload: trigger or consequence of mitochondrial oxidative stress in ventilator-induced diaphragmatic dysfunction?
Lecuona Emilia E Sassoon Catherine S CS Barreiro Esther E
American journal of respiratory and critical care medicine 20121201 11
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Project description:BackgroundDiabetes and obesity are associated with an increased risk of arrhythmia and sudden cardiac death. Abnormal lipid accumulation is observed in cardiomyocytes of obese and diabetic patients, which may contribute to arrhythmia, but the mechanisms are poorly understood. A transgenic mouse model of cardiac lipid overload, the peroxisome proliferator-activated receptor-γ (PPARg) cardiac overexpression mouse, has long QT and increased ventricular ectopy.ObjectiveThe purpose of this study was to evaluate the hypothesis that the increase in ventricular ectopy during cardiac lipid overload is caused by abnormalities in calcium handling due to increased mitochondrial oxidative stress.MethodsVentricular myocytes were isolated from adult mouse hearts to record sparks and calcium transients. Mice were implanted with heart rhythm monitors for in vivo recordings.ResultsPPARg cardiomyocytes have more frequent triggered activity and increased sparks compared to control. Sparks and triggered activity are reduced by mitotempo, a mitochondrial-targeted antioxidant. This is explained by a significant increase in oxidation of RyR2. Calcium transients are increased in amplitude, and sarcoplasmic reticulum (SR) calcium stores are increased in PPARg cardiomyocytes. Computer modeling of the cardiac action potential demonstrates that long QT contributes to increased SR calcium. Mitotempo decreased ventricular ectopy in vivo.ConclusionDuring cardiac lipid overload, mitochondrial oxidative stress causes increased SR calcium leak by oxidizing RyR2 channels. This promotes ventricular ectopy, which is significantly reduced in vivo by a mitochondrial-targeted antioxidant. These results suggest a potential role for mitochondrial-targeted antioxidants in preventing arrhythmia and sudden cardiac death in obese and diabetic patients.
| S-EPMC4958577 | biostudies-literature
Project description:Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.
| S-EPMC10509277 | biostudies-literature
Project description:IntroductionMechanical ventilation (MV) is a lifesaving procedure for critically ill patients. Diaphragm activation and stimulation may counteract side effects, such as ventilator-induced diaphragm dysfunction (VIDD). The effects of stimulation on diaphragm atrophy and patient outcomes are reported in this systematic review.Evidence acquisitionStudies investigating diaphragmatic stimulation versus standard of care in critically ill patients and evaluating clinical outcomes were extracted from a Medline database last on January 23, 2023, after registration in Prospero (CRD42021259353). Selected studies included the investigation of diaphragmatic stimulation versus standard of care in critically ill patients, an evaluation of the clinical outcomes. These included muscle atrophy, VIDD, weaning failure, mortality, quality of life, ventilation time, diaphragmatic function, length of stay in the Intensive Care Unit (ICU), and length of hospital stay. All articles were independently evaluated by two reviewers according to their abstract and title and, secondly, a full texts evaluation by two independent reviewers was performed. To resolve diverging evaluations, a third reviewer was consulted to reach a final decision. Data were extracted by the reviewers following the Oxford 2011 levels of evidence guidelines and summarized accordingly.Evidence synthesisSeven studies were extracted and descriptively synthesized, since a metanalysis was not feasible. Patients undergoing diaphragm stimulation had moderate evidence of higher maximal inspiratory pressure (MIP), less atrophy, less mitochondrial respiratory dysfunction, less oxidative stress, less molecular atrophy, shorter MV time, shorter ICU length of stay, longer survival, and better SF-36 scores than control.ConclusionsEvidence of the molecular and histological benefits of diaphragmatic stimulation is limited. The results indicate positive clinical effects of diaphragm activation with a moderate level of evidence for MIP and a low level of evidence for other outcomes. Diaphragm activation could be a therapeutic solution to avoid diaphragm atrophy, accelerate weaning, shorten MV time, and counteract VIDD; however, better-powered studies are needed to increase the level of evidence.
| S-EPMC10794987 | biostudies-literature
Project description:Side effects of mechanical ventilation, such as ventilator-induced diaphragmatic dysfunction (VIDD) and ventilator-induced lung injury (VILI), occur frequently in critically ill patients. Phrenic nerve stimulation (PNS) has been a valuable tool for diagnosing VIDD by assessing respiratory muscle strength in response to magnetic PNS. The detection of pathophysiologically reduced respiratory muscle strength is correlated with weaning failure, longer mechanical ventilation time, and mortality. Non-invasive electromagnetic PNS designed for diagnostic use is a reference technique that allows clinicians to measure transdiaphragm pressure as a surrogate parameter for diaphragm strength and functionality. This helps to identify diaphragm-related issues that may impact weaning readiness and respiratory support requirements, although lack of lung volume measurement poses a challenge to interpretation. In recent years, therapeutic PNS has been demonstrated as feasible and safe in lung-healthy and critically ill patients. Effects on critically ill patients' VIDD or diaphragm atrophy outcomes are the subject of ongoing research. The currently investigated application forms are diverse and vary from invasive to non-invasive and from electrical to (electro)magnetic PNS, with most data available for electrical stimulation. Increased inspiratory muscle strength and improved diaphragm activity (e.g., excursion, thickening fraction, and thickness) indicate the potential of the technique for beneficial effects on clinical outcomes as it has been successfully used in spinal cord injured patients. Concerning the potential for electrophrenic respiration, the data obtained with non-invasive electromagnetic PNS suggest that the induced diaphragmatic contractions result in airway pressure swings and tidal volumes remaining within the thresholds of lung-protective mechanical ventilation. PNS holds significant promise as a therapeutic intervention in the critical care setting, with potential applications for ameliorating VIDD and the ability for diaphragm training in a safe lung-protective spectrum, thereby possibly reducing the risk of VILI indirectly. Outcomes of such diaphragm training have not been sufficiently explored to date but offer the perspective for enhanced patient care and reducing weaning failure. Future research might focus on using PNS in combination with invasive and non-invasive assisted ventilation with automatic synchronisation and the modulation of PNS with spontaneous breathing efforts. Explorative approaches may investigate the feasibility of long-term electrophrenic ventilation as an alternative to positive pressure-based ventilation.
| S-EPMC10728426 | biostudies-literature
Project description:BackgroundKindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease.MethodsPatient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy.ResultsPatient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state.ConclusionsThis is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.
| S-EPMC4302591 | biostudies-literature
Project description:AimsWe investigate the role of mitochondrial oxidative stress in mitochondrial proteome remodelling using mouse models of heart failure induced by pressure overload.Methods and resultsWe demonstrate that mice overexpressing catalase targeted to mitochondria (mCAT) attenuate pressure overload-induced heart failure. An improved method of label-free unbiased analysis of the mitochondrial proteome was applied to the mouse model of heart failure induced by transverse aortic constriction (TAC). A total of 425 mitochondrial proteins were compared between wild-type and mCAT mice receiving TAC or sham surgery. The changes in the mitochondrial proteome in heart failure included decreased abundance of proteins involved in fatty acid metabolism, an increased abundance of proteins in glycolysis, apoptosis, mitochondrial unfolded protein response and proteolysis, transcription and translational control, and developmental processes as well as responses to stimuli. Overexpression of mCAT better preserved proteins involved in fatty acid metabolism and attenuated the increases in apoptotic and proteolytic enzymes. Interestingly, gene ontology analysis also showed that monosaccharide metabolic processes and protein folding/proteolysis were only overrepresented in mCAT but not in wild-type mice in response to TAC.ConclusionThis is the first study to demonstrate that scavenging mitochondrial reactive oxygen species (ROS) by mCAT not only attenuates most of the mitochondrial proteome changes in heart failure, but also induces a subset of unique alterations. These changes represent processes that are adaptive to the increased work and metabolic requirements of pressure overload, but which are normally inhibited by overproduction of mitochondrial ROS.
| S-EPMC3243039 | biostudies-literature
Project description:Diastolic dysfunction (DD) underlies heart failure with preserved ejection fraction (HFpEF), a clinical syndrome associated with aging that is becoming more prevalent. Despite extensive clinical studies, no effective treatment exists for HFpEF. Recent findings suggest that oxidative stress contributes to the pathophysiology of DD, but molecular mechanisms underpinning redox-sensitive cardiac remodeling in DD remain obscure. Using transgenic mice with mitochondria-targeted NOX4 overexpression (Nox4TG618) as a model, we demonstrate that NOX4-dependent mitochondrial oxidative stress induces DD in mice as measured by increased E/E', isovolumic relaxation time, Tau Glantz and reduced dP/dtmin while EF is preserved. In Nox4TG618 mice, fragmentation of cardiomyocyte mitochondria, increased DRP1 phosphorylation, decreased expression of MFN2, and a higher percentage of apoptotic cells in the myocardium are associated with lower ATP-driven and maximal mitochondrial oxygen consumption rates, a decrease in respiratory reserve, and a decrease in citrate synthase and Complex I activities. Transgenic mice have an increased concentration of TGFβ and osteopontin in LV lysates, as well as MCP-1 in plasma, which correlates with a higher percentage of LV myocardial periostin- and ACTA2-positive cells compared with wild-type mice. Accordingly, the levels of ECM as measured by Picrosirius Red staining as well as interstitial deposition of collagen I are elevated in the myocardium of Nox4TG618 mice. The LV tissue of Nox4TG618 mice also exhibited increased ICaL current, calpain 2 expression, and altered/disrupted Z-disc structure. As it pertains to human pathology, similar changes were found in samples of LV from patients with DD. Finally, treatment with GKT137831, a specific NOX1 and NOX4 inhibitor, or overexpression of mCAT attenuated myocardial fibrosis and prevented DD in the Nox4TG618 mice. Together, our results indicate that mitochondrial oxidative stress contributes to DD by causing mitochondrial dysfunction, impaired mitochondrial dynamics, increased synthesis of pro-inflammatory and pro-fibrotic cytokines, activation of fibroblasts, and the accumulation of extracellular matrix, which leads to interstitial fibrosis and passive stiffness of the myocardium. Further, mitochondrial oxidative stress increases cardiomyocyte Ca2+ influx, which worsens CM relaxation and raises the LV filling pressure in conjunction with structural proteolytic damage.
| S-EPMC9530618 | biostudies-literature
Project description:Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.
| S-EPMC11208592 | biostudies-literature
Project description:James Parkinson first described the motor symptoms of the disease that took his name over 200 years ago. While our knowledge of many of the changes that occur in this condition has increased, it is still unknown what causes this neurodegeneration and why it only affects some individuals with advancing age. Here we review current literature to discuss whether the mitochondrial dysfunction we have detected in Parkinson's disease is a pathogenic cause of neuronal loss or whether it is itself a consequence of dysfunction in other pathways. We examine research data from cases of idiopathic Parkinson's with that from model systems and individuals with familial forms of the disease. Furthermore, we include data from healthy aged individuals to highlight that many of the changes described are also present with advancing age, though not normally in the presence of severe neurodegeneration. While a definitive answer to this question may still be just out of reach, it is clear that mitochondrial dysfunction sits prominently at the centre of the disease pathway that leads to catastrophic neuronal loss in those affected by this disease.
| S-EPMC6627981 | biostudies-literature
Project description:The maintenance of mitochondrial respiratory function and homeostasis is essential to human health. Here, we identify condensin II subunits as novel regulators of mitochondrial respiration and mitochondrial stress responses. Condensin II is present in the nucleus and cytoplasm. While the effects of condensin II depletion on nuclear genome organization are well studied, the effects on essential cytoplasmic and metabolic processes are not as well understood. Excitingly, we observe that condensin II chromosome-associated protein (CAP) subunits individually localize to different regions of mitochondria, suggesting possible mitochondrial-specific functions independent from those mediated by the canonical condensin II holocomplex. Changes in cellular ATP levels and mitochondrial respiration are observed in condensin II CAP subunit-deficient cells. Surprisingly, we find that loss of NCAPD3 also sensitizes cells to oxidative stress. Together, these studies identify new, and possibly independent, roles for condensin II CAP subunits in preventing mitochondrial damage and dysfunction. These findings reveal a new area of condensin protein research that could contribute to the identification of targets to treat diseases where aberrant function of condensin II proteins is implicated.
| S-EPMC6899004 | biostudies-literature