In recent decades, several discoveries have been made that force us to reconsider old ideas about mitochondria and energy metabolism in the light of these discoveries. In this review, we discuss metabolic interaction between various organs, the metabolic significance of the primary substrates and their metabolic pathways, namely aerobic glycolysis, lactate shuttling, and fatty acids β-oxidation. We rely on the new ideas about the supramolecular structure of the mitochondrial respiratory chain (respirasome), the necessity of supporting substrates for fatty acids β-oxidation, and the reverse electron transfer via succinate dehydrogenase during β-oxidation.
View Article and Find Full Text PDFCell Mol Gastroenterol Hepatol
December 2024
Background: Hypertension is characterized by CD8 (cluster differentiation 8) T cell activation and infiltration into peripheral tissues. CD8 T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome.
View Article and Find Full Text PDFAm J Physiol Lung Cell Mol Physiol
May 2024
Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than nondeployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the subjects in this cohort reported exposure to sulfur dioxide (SO), we developed a model of repetitive exposure to SO in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease. Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO-exposed mice.
View Article and Find Full Text PDFSoldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the deployers in this cohort reported exposure to sulfur dioxide (SO ), we developed a model of repetitive exposure to SO in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular disease (PVD). Although abnormalities in small airways were not sufficient to alter lung mechanics, PVD was associated with the development of pulmonary hypertension and reduced exercise tolerance in SO exposed mice.
View Article and Find Full Text PDFPurpose: Patients with hyper- vs. hypo-inflammatory subphenotypes of acute respiratory distress syndrome (ARDS) exhibit different clinical outcomes. Inflammation increases the production of reactive oxygen species (ROS) and increased ROS contributes to the severity of illness.
View Article and Find Full Text PDFIn the past century, the lifespan of the human population has dramatically increased to the 80 s, but it is hindered by a limited health span to the 60 s due to an epidemic increase in the cardiovascular disease which is a main cause of morbidity and mortality. We cannot underestimate the progress in understanding the major cardiovascular risk factors which include cigarette smoking, dietary, and sedentary lifestyle risks. Despite their clinical significance, these modifiable risk factors are still the major contributors to cardiovascular disease.
View Article and Find Full Text PDFp53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal adenocarcinoma, we find that p53 protein is adducted with reactive isolevuglandins (isoLGs), products of lipid peroxidation.
View Article and Find Full Text PDFScientists have long established that fatty acids are the primary substrates for kidney mitochondria. However, to date we still do not know how long-chain and middle-chain fatty acids are oxidized at the mitochondrial level. Our previous research has shown that mitochondria from the heart, brain, and kidney oxidize palmitoylcarnitine at a high rate only in the presence of succinate, glutamate, or pyruvate.
View Article and Find Full Text PDFIntroduction: Perioperative alterations in perfusion lead to ischemia and reperfusion injury, and supplemental oxygen is administered during surgery to limit hypoxic injury but can lead to hyperoxia. We hypothesized that hyperoxia impairs endothelium-dependent and endothelium-independent vasodilation but not the vasodilatory response to heme-independent soluble guanylyl cyclase activation. Methods: We measured the effect of oxygen on vascular reactivity in mouse aortas.
View Article and Find Full Text PDFFront Cardiovasc Med
July 2022
Superoxide radical plays an important role in redox cell signaling and physiological processes; however, overproduction of superoxide or insufficient activity of antioxidants leads to oxidative stress and contributes to the development of pathological conditions such as endothelial dysfunction and hypertension. Meanwhile, the studies of superoxide in biological systems represent unique challenges associated with short lifetime of superoxide, insufficient reactivity of the superoxide probes, and lack of site-specific detection of superoxide. In this work we have developed N-and deuterium-enriched spin probe N-CAT1H for high sensitivity and site-specific detection of extracellular superoxide.
View Article and Find Full Text PDFMitochondrial dysfunctions caused by oxidative stress are currently regarded as the main cause of aging. Accumulation of mutations and deletions of mtDNA is a hallmark of aging. So far, however, there is no evidence that most studied oxygen radicals are directly responsible for mutations of mtDNA.
View Article and Find Full Text PDFRationale: Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.
View Article and Find Full Text PDFT and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension.
View Article and Find Full Text PDFAntioxid Redox Signal
October 2019
Vascular dysfunction plays a key role in the development of arteriosclerosis, heart disease, and hypertension, which causes one-third of deaths worldwide. Vascular oxidative stress and metabolic disorders contribute to vascular dysfunction, leading to impaired vasorelaxation, vascular hypertrophy, fibrosis, and aortic stiffening. Mitochondria are critical in the regulation of metabolic and antioxidant functions; therefore, mitochondria-targeted treatments could be beneficial.
View Article and Find Full Text PDFMitochondria are the major source of superoxide radicals and superoxide overproduction contributes to cardiovascular diseases and metabolic disorders. Endothelial dysfunction and diminished nitric oxide levels are early steps in the development of these pathological conditions. It is known that physiological production of nitric oxide reduces oxidative stress and inflammation, however, the precise mechanism of "antioxidant" effect of nitric oxide is not clear.
View Article and Find Full Text PDFBiochem Biophys Res Commun
January 2018
Background: Increased endothelial permeability is central to shock and organ dysfunction in sepsis but therapeutics targeted to known mediators of increased endothelial permeability have been unsuccessful in patient studies. We previously reported that cell-free hemoglobin (CFH) is elevated in the majority of patients with sepsis and is associated with organ dysfunction, poor clinical outcomes and elevated markers of oxidant injury. Others have shown that Vitamin C (ascorbate) may have endothelial protective effects in sepsis.
View Article and Find Full Text PDFNitroxides are widely used in biology as antioxidants, spin labels, functional spin probes for pH, oxygen and thiol levels, and tissue redox status imaging using electron paramagnetic resonance (EPR); however, biological applications of nitroxides is hindered by fast bioreduction to EPR-silent hydroxylamines and rapid clearance. In this work, we have studied pyrrolidine nitroxides with acetoxymethoxycarbonyl groups which can undergo hydrolysis by cellular esterases to hydrophilic carboxylate derivatives resistant to bioreduction. Nitroxides containing acetoxymethoxycarbonyl groups were rapidly absorbed by cells from the media, 3,4-bis-(acetoxymethoxycarbonyl)-proxyl (DCP-AM2) and 3-(2-(bis(2-(acetoxymethoxy)-2-oxoethyl)amino)acetamido)-proxyl (DCAP-AM2) showing the strongest EPR signal of the cellular fraction.
View Article and Find Full Text PDFEndothelial dysfunction, characterized by changes in eNOS, is a common finding in chronic inflammatory vascular diseases. These states are associated with increased infectious complications. We hypothesized that alterations in eNOS would enhance the response to LPS-mediated TLR4 inflammation.
View Article and Find Full Text PDFSignificance: Oxidative stress contributes to numerous pathophysiological conditions such as development of cancer, neurodegenerative, and cardiovascular diseases. A variety of measurements of oxidative stress markers in biological systems have been developed; however, many of these methods are not specific, can produce artifacts, and do not directly detect the free radicals and reactive oxygen species (ROS) that cause oxidative stress. Electron paramagnetic resonance (EPR) is a unique tool that allows direct measurements of free radical species.
View Article and Find Full Text PDFGastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A).
View Article and Find Full Text PDFRationale: Clinical studies have shown that Sirt3 (Sirtuin 3) expression declines by 40% by 65 years of age paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 because of increased NADH (nicotinamide adenine dinucleotide, reduced form) and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) because of hyperacetylation.
Objective: In this study, we examined whether the loss of Sirt3 activity increases vascular oxidative stress because of SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension.