Mechanistic study of the novel peroxidase mimetic DhHP-6 in metabolic cataracts.

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.

Over the past 10 to 15 years, a vast collection of studies have provided evidence indicating that reactive oxygen species (ROS), particularly superoxide (O2·−) and hydrogen peroxide (H2O2), contribute to the pathogenesis of cardiovascular diseases, such as heart failure and hypertension. Griendling et al1 first demonstrated that NADPH oxidase present in the vasculature is a primary source of the elevated ROS levels. Since these initial studies, NADPH oxidase-derived ROS in the kidney,2 heart,3 and brain4 have been linked to the development and progression of numerous cardiovascular-related diseases. More recently, however, mitochondria have also been identified as important sources of ROS in controlling cardiovascular function. Considering that mitochondria are the primary source of ROS in most cells during normal respiration because of the leaking of electrons from the electron transport chain (ETC), perhaps it should not be all that surprising that mitochondrial-produced ROS are involved in pathophysiological conditions of the cardiovascular system. To date, most of the evidence linking mitochondrial dysfunction and mitochondrial-produced ROS to the pathogenesis of cardiovascular diseases comes from studies on the peripheral renin-angiotensin system.5 For example, using a model of cardiac ischemic reperfusion injury, Kimura et al6 reported that angiotensin II (Ang II)-induced preconditioning is mediated by mitochondrial-produced ROS. The authors further demonstrated that Ang II-induced NADPH oxidase-derived ROS lie upstream of mitochondrial-produced ROS, thus, implicating a ROS-induced ROS mechanism. Similarly, it was demonstrated recently that, in aortic endothelial cells, Ang II-induced NADPH oxidase activation leads to an increase in mitochondrial ROS production, as well as mitochondrial dysfunction, as determined by a decrease in mitochondrial membrane potential and mitochondrial respiration.7 Together, these studies and others (detailed elsewhere5) clearly illustrate a role for mitochondrial-produced ROS and mitochondrial dysfunction in peripheral tissues in the pathogenesis of …

Multivitamin and mineral supplementation modulates oxidative stress and antioxidant vitamin levels in serum and follicular fluid of women undergoing in vitro fertilization

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging.

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia.

Diabetic neutrophil mitochondrial dysfunction: An inflammatory situation?

Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins

The tubule pathology of septic acute kidney injury: a neglected area of research comes of age

SOD2 in platelets: with age comes responsibility

CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction

BACKGROUND: Mitochondrial function and behavior are central to the physiology of humans and, consequently, "mitochondrial dysfunction" has been implicated in a wide range of disease.CONTENT: Mitochondrial ROS might attack various mitochondrial constituents, causing mitochondrial DNA mutations and oxidative damage to respiratory enzymes. A defect in mitochondrial respiratory enzymes would increase mitochondrial production of ROS, causing further mitochondrial damage and dysfunction. Mitochondrial dysfunction is associated with diseases, such as neurodegenerative disorders, cardiomyopathies, metabolic syndrome, obesity, and cancer. Pathways that improve mitochondrial function, attenuate mitochondrial oxidative stress, and regulate mitochondrial biogenesis have recently emerged as potential therapeutic targets.SUMMARY: Mitochondria perform diverse yet interconnected functions, produce ATP and many biosynthetic intermediates while also contribute to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. It is therefore not suprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative, cancer, and metabolic disorders. Interventions that modulate processes involved in regulation of mitochondrial turnover, with calorie restriction and induction of mitochondrial biogenesis, are of particular interest.KEYWORDS: mitochondrial biogenesis, mitochondrial dysfunction, reactive oxygen species (ROS), metabolic diseases

Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.

Mitochondrial metabolism in TCA cycle mutant cancer cells

An unavoidable consequence of aerobic respiration is the generation of reactive oxygen species (ROS). ROS is a collective term that includes both oxygen radicals and certain oxidizing agents that are easily converted into radicals. They can be produced from both endogenous and exogenous substances. ROS play a dual role in biological systems, since they can be either harmful or beneficial to living systems. They can be considered a double-edged sword: oxygen-dependent reactions and aerobic respiration have significant advantages but overproduction of ROS, a consequence of oxygen-dependent reactions, has the potential to cause damage. Overproduction of ROS may negatively impact neonatal growth and contribute to the aetiology of many developmental disorders. During mitochondrial respiration, an inability to neutralize reactive oxygen species and free radicals leads to oxidative stress. The inner membrane of the mitochondria contains a large number of free radical scavengers including glutathione, vitamin C, and vitamin E, as well as anti-oxidant enzymes such as superoxide dismutase. The brain is particularly vulnerable to free radical attack for several reasons, including exposed to high oxygen concentrations, relatively low antioxidant protection, membranes with high levels of polyunsaturated fatty acids, and high iron and ascorbate content. The brain's high energy demand is primarily supplied by oxidative phosphorylation, the major producer of free radicals. When the level of free radicals overwhelms the cellular antioxidant defense system, a deleterious condition known as oxidative stress occurs. ROS has an intimate relationship with mitochondrial function and oxidative stress is believed to result from mitochondrial dysfunction. This review highlights the role of oxidative stress and mitochondrial dysfunction as key players in the neurodevelopmental pathophysiology. The mechanisms associating these two disease states can lead to neuronal death, neuroinflammation and impairment of energy metabolism. Biomarkers related to both aspects will be highlighted to demonstrate their importance in the early diagnosis of neurodevelopmental disorders like autism, cerebral palsy and others. Treatments trials for oxidative stress or mitochondrial dysfunction using nutritional supplements and antioxidants are reviewed in order to shed light on recent strategies for the early intervention for neurodevelopmental disorders.