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Regulation of mtROS production. A number of factors including mitochondrial membrane potential (Δψm), metabolic state of mitochondrial, O2 concentration regulate the production of mtROS. Non-mitochondrial generated ROS can also augment mtROS production, a process known as “ROS-induced ROS”. Meanwhile, transcription factor STAT3 has recently been found to suppress mtROS production independent of its nuclear factor activity.

Regulation of mtROS production. A number of factors including mitochondrial membrane potential (Δψm), metabolic state of mitochondrial, O2 concentration regulate the production of mtROS. Non-mitochondrial generated ROS can also augment mtROS production, a process known as “ROS-induced ROS”. Meanwhile, transcription factor STAT3 has recently been found to suppress mtROS production independent of its nuclear factor activity.

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There are multiple sources of reactive oxygen species (ROS) in the cell. As a major site of ROS production, mitochondria have drawn considerable interest because it was recently discovered that mitochondrial ROS (mtROS) directly stimulate the production of proinflammatory cytokines and pathological conditions as diverse as malignancies, autoimmune...

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... Mitochondria are major cellular energy generators found in all nucleated hum types. In addition to their primary role of generating ATP by oxidative phospho (OXPHOS) they play vital roles in calcium and iron homeostasis, and regulating processes including ROS generation, inflammation and apoptosis [8]. Howeve chondrial dysfunction can develop and is found in a broad range of diseases in cancer, neurodegeneration and atherosclerosis. ...
... Mitochondria are major cellular energy generators found in all nucleated human cell types. In addition to their primary role of generating ATP by oxidative phosphorylation (OXPHOS) they play vital roles in calcium and iron homeostasis, and regulating critical processes including ROS generation, inflammation and apoptosis [8]. However, mitochondrial dysfunction can develop and is found in a broad range of diseases including cancer, neurodegeneration and atherosclerosis. ...
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Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
... These overproduced superoxide anions are endogenously controlled by superoxide dismutase (SOD) via their conversion into hydrogen peroxide, which in turn is converted into water by catalase or peroxidase enzymes. However, in various diseases such as neurological diseases, cardiovascular disorders, and autoimmune diseases, a disturbance of this redox balance occurs in mitochondria, which activates inflammasomes, RIG-I-like receptors (RLRs), and mitogen-activated protein kinases (MAPK), leading to the activation of innate immune and inflammatory responses [14]. Numerous anti-oxidants such as coenzyme Q10 [15], vitamin E [16], apocynin [17], and SOD mimetic [18] in conjugation with small cationic molecules such as triphenylphosphonium (TPP + ) have been used in controlling imbalanced redox species in mitochondria. ...
... Pharmaceutics 2022,14, 2657 ...
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Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria are considered a novel and promising therapeutic target for the diagnosis, treatment, and prevention of various human diseases including metabolic disorders, cancer, and neurodegenerative diseases. For mitochondria-targeted therapy, there is a need to develop an effective drug delivery approach, owing to the mitochondrial special bilayer structure through which therapeutic molecules undergo multiple difficulties in reaching the core. In recent years, various nanoformulations have been designed such as polymeric nanoparticles, liposomes, inorganic nanoparticles conjugate with mitochondriotropic moieties such as mitochondria-penetrating peptides (MPPs), triphenylphosphonium (TPP), dequalinium (DQA), and mitochondrial protein import machinery for overcoming barriers involved in targeting mitochondria. The current approaches used for mitochondria-targeted drug delivery have provided promising ways to overcome the challenges associated with targeted-drug delivery. Herein, we review the research from past years to the current scenario that has identified mitochondrial dysfunction as a major contributor to the pathophysiology of various diseases. Furthermore, we discuss the recent advancements in mitochondria-targeted drug delivery strategies for the pathologies associated with mitochondrial dysfunction.
... Meanwhile, abnormal pH values in these organelles are related to cellular dysfunctions and many diseases, including cancer and neurodegenerative disorders [10][11][12]. Mitochondria function primarily as important organelles that provide a myriad of metabolic functions, including energy production through the respiratory chain [13], cell signaling through cellular reactive oxygen species (ROS) [14,15] production, regulation of Ca 2+ homeostasis [16,17], and initiation of cellular apoptosis [18]. Abnormal pH can cause mitochondrial dysfunction and even severe diseases [19,20]. ...
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pH plays a crucial role in cells, especially mitochondria, an important organelle. Developing probes with well-performance for pH detection is still in great demand. Therefore, we first synthesized an indole-based probe (MC-ID-OL) to detect mitochondrial pH changes. The emission wavelength of MC-ID-OL is 649 nm, which does not reach the near-infrared region (650–900 nm). To further enlarge the emission wavelength, probe MC-BI-OL was developed by replacing indolenine with benzoindole. As expected, the emission wavelength changed from 649 to 656 nm. MC-BI-OL probes could also detect pH changes and mitochondria's highly reversible proportional fluorescence localization. In addition, the fluorescence imaging of the MC-BI-OL in HeLa cells demonstrated that this probe could sense changes in the pH of mitochondria in cells.
... MDA inhibits the nucleotide repair system resulting in DNA becoming more susceptible to mutations, making it easier to destroy. In addition, these increased levels also cause damage to mitochondrial DNA, increasing the levels of mitochondrial ROS (ROS produced by the mit ETC chain, as there are multiple sources of ROS in the cell) while decreasing mitochondrial antioxidant levels [71,72]. Therefore, oxidative stress can damage fatty acids, which in turn cause lipid peroxidation and damage to brain cell membranes. ...
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Background: Increasing evidence suggests that the presence of oxidative stress and disorders of the antioxidant defense system are involved in a wide range of neuropsychiatric disorders, such as bipolar disorder, schizophrenia and major depression, but the exact mechanism remains unknown. This review focuses on a better appreciation of the contribution of oxidative stress to depression and bipolar disorder. Methods: This review was conducted by extracting information from other research and review studies, as well as other meta-analyses, using two search engines, PubMed and Google Scholar. Results: As far as depression is concerned, there is agreement among researchers on the association between oxidative stress and antioxidants. In bipolar disorder, however, most of them observe strong lipid peroxidation in patients, while regarding antioxidant levels, opinions are divided. Nevertheless, in recent years, it seems that on depression, there are mainly meta-analyses and reviews, rather than research studies, unlike on bipolar disorder. Conclusions: Undoubtedly, this review shows that there is an association among oxidative stress, free radicals and antioxidants in both mental disorders, but further research should be performed on the exact role of oxidative stress in the pathophysiology of these diseases.
... Many signaling pathways in inflammation are regulated by mitochondria and may have a role in COVID-19 pathology [33,136]. Mitochondrial reactive oxygen species (ROS) are potent oxidizers that can directly damage DNA, proteins, and lipids or activate downstream pathways that promote inflammation and endothelial dysfunction [13,137]. The infection of ECs by SARS-CoV-2 might contribute to mitochondrial dysfunction and enhanced oxidative stress, possibly initiating a feedback loop that promotes chronic inflammation and endothelial damage even after the virus has been cleared. ...
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Although COVID-19 is primarily a respiratory disease, it may affect also the cardiovascular system. COVID-19 patients with cardiovascular disorder (CVD) develop a more severe disease course with a significantly higher mortality rate than non-CVD patients. A common denominator of CVD is the dysfunction of endothelial cells (ECs), increased vascular permeability, endothelial-to-mesenchymal transition, coagulation, and inflammation. It has been assumed that clinical complications in COVID-19 patients suffering from CVD are caused by SARS-CoV-2 infection of ECs through the angiotensin-converting enzyme 2 (ACE2) receptor and the cellular transmembrane protease serine 2 (TMPRSS2) and the consequent dysfunction of the infected vascular cells. Meanwhile, other factors associated with SARS-CoV-2 entry into the host cells have been described, including disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), the C-type lectin CD209L or heparan sulfate proteoglycans (HSPG). Here, we discuss the current data about the putative entry of SARS-CoV-2 into endothelial and smooth muscle cells. Furthermore, we highlight the potential role of long non-coding RNAs (lncRNAs) affecting vascular permeability in CVD, a process that might exacerbate disease in COVID-19 patients.
... Another issue that has been studied is the interaction between inflammation and oxidative stress (Saleh et al., 2020). TNF-α induces an increase in mitochondrial ROS, also modulated by IL-6, which impairs the activity of the electron transport chain and further stimulates the production of proinflammatory cytokines (Li et al., 2013;Saleh et al., 2020). The cytokines present in patients during coronavirus infection may prevent oxidative phosphorylation and ATP in cellular mitochondria, which could cause membrane permeabilization, changes in mitochondrial dynamics, ROS production, and cell death by apoptosis (Naik and Dixit, 2011;Jo et al., 2016;Saleh et al., 2020). ...
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Coronavirus disease 2019 (COVID-19) is triggered by the SARS-CoV-2, which is able to infect and cause dysfunction not only in lungs, but also in multiple organs, including central nervous system, skeletal muscle, kidneys, heart, liver, and intestine. Several metabolic disturbances are associated with cell damage or tissue injury, but the mechanisms involved are not yet fully elucidated. Some potential mechanisms involved in the COVID-19- induced tissue dysfunction are proposed, such as: (a) High expression and levels of proinflammatory cytokines, including TNF-α IL-6, IL-1β, INF-α and INF-β, increasing the systemic and tissue inflammatory state; (b) Induction of oxidative stress due to redox imbalance, resulting in cell injury or death induced by elevated production of reactive oxygen species; and (c) Deregulation of the renin-angiotensin-aldosterone system, exacerbating the inflammatory and oxidative stress responses. In this review, we discuss the main metabolic disturbances observed in different target tissues of SARS-CoV-2 and the potential mechanisms involved in these changes associated with the tissue dysfunction.
... Under normal conditions, Ca 2+ promotes the Kreb cycle that consumes more oxygen and increases ROS levels, which is under fine-tune modulated 42 . However, when mitochondria are overloaded with Ca 2+ , ROS production can be generated independent of the metabolic state 43 . Importantly, ROS levels are required for normal cellular functions and only high amount of ROS results in cell damage 41 . ...
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Paraquat (PQ) is an efficient herbicide but leads to high mortality with no antidote in mammals. PQ produces reactive oxygen species (ROS), leading to epithelial-mesenchymal transition (EMT) for pulmonary fibrosis in type II alveolar (AT II) cells. Intriguingly, strategies reducing ROS exhibit limited therapeutic effects, indicating other targets existing for PQ toxicity. Herein we report that PQ is also an agonist for STIM1 that increases intracellular calcium levels. Particularly, PQ promotes STIM1 puncta formation and association with TRPC1 or ORAI for extracellular calcium entry and thus intracellular calcium influx. Further studies reveal the importance of P584&Y586 residues in STIM1 for PQ association that facilitates STIM1 binding to TRPC1. Consequently, the STIM1-TRPC1 route facilitates PQ-induced EMT for pulmonary fibrosis as well as cell death. Our results demonstrate that PQ is an agonist of STIM1 that induces extracellular calcium entry, increases intracellular calcium levels, and thus promotes EMT in AT II cells.
... Metabolites produced by ATP synthesis, including nucleic acids, lipids, and proteins, are used for macromolecule biosynthesis. Mitochondria also provide the majority of reactive oxygen species (ROS), and the bulk of mitochondrial ROS is produced in the electron transport chain (ETC) [12][13][14]. Therefore, dysfunctional mitochondria act as harmful ROS generators, causing oxidative stress and triggering apoptosis and cell damage. ...
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Mitochondria are highly dynamic cellular organelles that perform crucial functions such as respiration, energy production, metabolism, and cell fate decisions. Mitochondrial damage and dysfunction critically lead to the pathogenesis of various diseases including cancer, diabetes, and neurodegenerative and cardiovascular disorders. Mitochondrial damage in response to environmental contaminant exposure and its association with the pathogenesis of diseases has also been reported. Recently, persistent pollutants, such as micro- and nanoplastics, have become growing global environmental threats with potential health risks. In this review, we discuss the impact of micro- and nanoplastics on mitochondria and review current knowledge in this field.
... Moreover, we found antioxidative genes downregulated in renal TECs treated with glutamine, showing a reduced state of oxidative stress in these cells. In addition, we further substantiate glutamine's protective effects on oxidative stress management as we demonstrate that glutamine decreased mROS release, which are mainly produced at the electron transport chain during the oxidative phosphorylation process (49,50). This finding is in accordance with a previous study of glutamine alleviating kidney lipid peroxides' production in a polymicrobial sepsis mouse model induced by cecal ligation and puncture (51). ...
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Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia-reperfusion-injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, neutrophil recruitment and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Furthermore, the direct modulation of the Tgm2-HSP70 signalosome and reduced Ask1 activation result in decreased JNK activation leading to diminished mitochondrial intrinsic apoptosis in TECs. Glutamine administration attenuated kidney damage in vivo during AKI and TEC viability in vitro under inflammatory or hypoxic conditions.
... A high level of ROS increases membrane permeability and induces disruption of MMP (Li et al., 2013). MMP, a consequence of the electrochemical proton gradient maintained for ATP synthesis, is an important indicator of functional mitochondria (Perry et al., 2011). ...
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Pancreatic cancer is an aggressive cancer characterized by high mortality and poor prognosis, with a survival rate of less than 5 years in advanced stages. Ivermectin, an antiparasitic drug, exerts antitumor effects in various cancer types. This is the first study to evaluate the anticancer effects of the combination of ivermectin and gemcitabine in pancreatic cancer. We found that the ivermectin–gemcitabine combination treatment suppressed pancreatic cancer more effectively than gemcitabine alone treatment. The ivermectin–gemcitabine combination inhibited cell proliferation via G1 arrest of the cell cycle, as evidenced by the downregulation of cyclin D1 expression and the mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT-3) signaling pathway. Ivermectin–gemcitabine increased cell apoptosis by inducing mitochondrial dysfunction via the overproduction of reactive oxygen species and decreased the mitochondrial membrane potential. This combination treatment also decreased the oxygen consumption rate and inhibited mitophagy, which is important for cancer cell death. Moreover, in vivo experiments confirmed that the ivermectin–gemcitabine group had significantly suppressed tumor growth compared to the gemcitabine alone group. These results indicate that ivermectin exerts synergistic effects with gemcitabine, preventing pancreatic cancer progression, and could be a potential antitumor drug for the treatment of pancreatic cancer.