scholarly journals Coenzyme Q at the Hinge of Health and Metabolic Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1785
Author(s):  
Juan Diego Hernández-Camacho ◽  
Laura García-Corzo ◽  
Daniel José Moreno Fernández-Ayala ◽  
Plácido Navas ◽  
Guillermo López-Lluch
Keyword(s):  
Oxidative Stress ◽  
Metabolic Diseases ◽  
Coenzyme Q ◽  
Redox Homeostasis ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Deficiency Syndrome ◽  
Plasma Lipoproteins ◽  
Mitochondrial Oxidative Stress ◽  
Key Factor

Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging.

scholarly journals The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Longman Li ◽  
Xiaobo Yang
Keyword(s):  
Oxidative Stress ◽  
Metabolic Diseases ◽  
Essential Element ◽  
Ros Generation ◽  
Oxygen Species ◽  
Mitochondrial Oxidative Stress ◽  
Nonalcoholic Fatty Liver ◽  
The Past ◽  
The Relationship

Manganese (Mn) is an essential element that is involved in the synthesis and activation of many enzymes and in the regulation of the metabolism of glucose and lipids in humans. In addition, Mn is one of the required components for Mn superoxide dismutase (MnSOD) that is mainly responsible for scavenging reactive oxygen species (ROS) in mitochondrial oxidative stress. Both Mn deficiency and intoxication are associated with adverse metabolic and neuropsychiatric effects. Over the past few decades, the prevalence of metabolic diseases, including type 2 diabetes mellitus (T2MD), obesity, insulin resistance, atherosclerosis, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and hepatic steatosis, has increased dramatically. Previous studies have found that ROS generation, oxidative stress, and inflammation are critical for the pathogenesis of metabolic diseases. In addition, deficiency in dietary Mn as well as excessive Mn exposure could increase ROS generation and result in further oxidative stress. However, the relationship between Mn and metabolic diseases is not clear. In this review, we provide insights into the role Mn plays in the prevention and development of metabolic diseases.

scholarly journals Design of High-Throughput Screening of Natural Extracts to Identify Molecules Bypassing Primary Coenzyme Q Deficiency in Saccharomyces cerevisiae

2019 ◽  
Vol 25 (3) ◽  
pp. 299-309
Author(s):  
Aida M. Berenguel Hernández ◽  
Mercedes de la Cruz ◽  
María Alcázar-Fabra ◽  
Andrés Prieto-Rodríguez ◽  
Ana Sánchez-Cuesta ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Coenzyme Q ◽  
Genetic Disorders ◽  
Screening Method ◽  
Mitochondrial Diseases ◽  
Deficiency Syndrome ◽  
Natural Extracts ◽  
Representative Subset ◽  
Nonfermentable Carbon Source

Coenzyme Q10 (CoQ10) deficiency syndrome is a rare disease included in the family of mitochondrial diseases, which is a heterogeneous group of genetic disorders characterized by defective energy production. CoQ10 biosynthesis in humans requires at least 11 gene products acting in a multiprotein complex within mitochondria. The high-throughput screening (HTS) method based on the stabilization of the CoQ biosynthesis complex (Q-synthome) produced by the COQ8 gene overexpression is proven here to be a successful method for identifying new molecules from natural extracts that are able to bypass the CoQ6 deficiency in yeast mutant cells. The main features of the new approach are the combination of two yeast targets defective in genes with different functions on CoQ6 biosynthesis to secure the versatility of the molecule identified, the use of glycerol as a nonfermentable carbon source providing a wide growth window, and the stringent conditions required to mark an extract as positive. The application of this pilot approach to a representative subset of 1200 samples of the Library of Natural Products of Fundación MEDINA resulted in the finding of nine positive extracts. The fractionation of three of the nine extracts allowed the identification of five molecules; two of them are present in molecule databases of natural extracts and three are nondescribed molecules. The use of this screening method opens the possibility of discovering molecules with CoQ10-bypassing action useful as therapeutic agents to fight against mitochondrial diseases in human patients.

scholarly journals Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1101
Author(s):  
Mei-Chun Chen ◽  
Li-Lin Hsu ◽  
Sheng-Fan Wang ◽  
Yi-Ling Pan ◽  
Jeng-Fan Lo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Redox Homeostasis ◽  
Glucose Deprivation ◽  
Metabolic Flexibility ◽  
Mitochondrial Oxidative Stress ◽  
Cancer Cell Death ◽  
Adaptation Response

Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.

Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells

2015 ◽  
Vol 308 (11) ◽  
pp. E933-E941 ◽  
Author(s):  
Tuyet Thi Nguyen ◽  
Xianglan Quan ◽  
Kyu-Hee Hwang ◽  
Shanhua Xu ◽  
Ranjan Das ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Stress Proteins ◽  
Mitochondrial Permeability Transition ◽  
Islet Cells ◽  
Atp Synthesis ◽  
Permeability Transition ◽  
Insulin Content ◽  
Superoxide Generation ◽  
Mitochondrial Oxidative Stress

Inorganic phosphate (P i) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, P i transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated P i concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have investigated the effect of P i on secretory function and apoptosis in INS-1E clonal β-cells and rat pancreatic islets. Elevated extracellular P i (1∼5 mM) increased the mitochondrial membrane potential (ΔΨm), superoxide generation, caspase activation, and cell death. Depolarization of the ΔΨm abolished P i-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented ΔΨm hyperpolarization, superoxide generation, and cytotoxicity caused by P i. High P i also promoted the opening of the mitochondrial permeability transition (PT) pore, leading to apoptosis, which was also prevented by butylmalonate. The mitochondrial antioxidants mitoTEMPO or MnTBAP prevented P i-triggered PT pore opening and cytotoxicity. Elevated extracellular P i diminished ATP synthesis, cytosolic Ca2+ oscillations, and insulin content and secretion in INS-1E cells as well as in dispersed islet cells. These parameters were restored following preincubation with mitochondrial antioxidants. This treatment also prevented high-P i-induced phosphorylation of ER stress proteins. We propose that elevated extracellular P i causes mitochondrial oxidative stress linked to mitochondrial hyperpolarization. Such stress results in reduced insulin content and defective insulin secretion and cytotoxicity. Our data explain the decreased insulin content and secretion observed under hyperphosphatemic states.

scholarly journals Mitochondrial Dysfunction in Metabolic Disease

2012 ◽  
Vol 4 (3) ◽  
pp. 119
Author(s):  
Anna Meiliana ◽  
Andi Wijaya
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Stress Responses ◽  
Metabolic Diseases ◽  
Respiratory Enzymes ◽  
Mitochondrial Oxidative Stress ◽  
Cancer Pathways ◽  
Wide Range ◽  
Key Factor

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

scholarly journals CG8005 Mediates Transit-Amplifying Spermatogonial Divisions via Oxidative Stress in Drosophila Testes

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Wanyin Chen ◽  
Xiaojin Luan ◽  
Yidan Yan ◽  
Min Wang ◽  
Qianwen Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Mrna Expression ◽  
Genetic Manipulation ◽  
Redox Homeostasis ◽  
Cell Activity ◽  
Ros Generation ◽  
S2 Cells ◽  
Key Factor

The generation of reactive oxygen species (ROS) widely occurs in metabolic reactions and affects stem cell activity by participating in stem cell self-renewal. However, the mechanisms of transit-amplifying (TA) spermatogonial divisions mediated by oxidative stress are not fully understood. Through genetic manipulation of Drosophila testes, we demonstrated that CG8005 regulated TA spermatogonial divisions and redox homeostasis. Using in vitro approaches, we showed that the knockdown of CG8005 increased ROS levels in S2 cells; the induced ROS generation was inhibited by NAC and exacerbated by H2O2 pretreatments. Furthermore, the silencing of CG8005 increased the mRNA expression of oxidation-promoting factors Keap1, GstD1, and Mal-A6 and decreased the mRNA expression of antioxidant factors cnc, Gclm, maf-S, ND-42, and ND-75. We further investigated the functions of the antioxidant factor cnc, a key factor in the Keap1-cnc signaling pathway, and showed that cnc mimicked the phenotype of CG8005 in both Drosophila testes and S2 cells. Our results indicated that CG8005, together with cnc, controlled TA spermatogonial divisions by regulating oxidative stress in Drosophila.

scholarly journals The Paradox of Coenzyme Q10 in Aging

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2221 ◽  
Author(s):  
Díaz-Casado ◽  
Quiles ◽  
Barriocanal-Casado ◽  
González-García ◽  
Battino ◽  
...  
Keyword(s):  
Coenzyme Q10 ◽  
Biosynthetic Pathway ◽  
Metabolic Diseases ◽  
Coenzyme Q ◽  
Deficiency Syndrome ◽  
Mitochondrial Inner Membrane ◽  
Therapeutic Benefits ◽  
Redox Capacity ◽  
Coq10 Supplementation ◽  
Human And Mouse

Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q10 (CoQ10) supplementation has shown benefits as an anti-aging agent, especially under certain conditions associated with increased oxidative stress. Also, CoQ10 has shown therapeutic benefits in aging-related disorders, particularly in cardiovascular and metabolic diseases. Thus, we discuss the paradox of health benefits due to a defect in the CoQ biosynthetic pathway or exogenous supplementation of CoQ10.

scholarly journals Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1083
Author(s):  
Emanuela Bottani ◽  
Costanza Lamperti ◽  
Alessandro Prigione ◽  
Valeria Tiranti ◽  
Nicola Persico ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Metabolic Diseases ◽  
Primary Source ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Clinical Results ◽  
Limited Information ◽  
Large Variability ◽  
Genes Encoding ◽  
Organ Specific

Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.

scholarly journals Targeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1142 ◽  
Author(s):  
Josh Williamson ◽  
Gareth Davison
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Nuclear Dna ◽  
Redox Homeostasis ◽  
Human Longevity ◽  
Antioxidant Compounds ◽  
Special Focus ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Superoxide ◽  
Exercise Induced

Exercise simultaneously incites beneficial (e.g., signal) and harming (e.g., damage to macromolecules) effects, likely through the generation of reactive oxygen and nitrogen species (RONS) and downstream changes to redox homeostasis. Given the link between nuclear DNA damage and human longevity/pathology, research attempting to modulate DNA damage and restore redox homeostasis through non-selective pleiotropic antioxidants has yielded mixed results. Furthermore, until recently the role of oxidative modifications to mitochondrial DNA (mtDNA) in the context of exercising humans has largely been ignored. The development of antioxidant compounds which specifically target the mitochondria has unveiled a number of exciting avenues of exploration which allow for more precise discernment of the pathways involved with the generation of RONS and mitochondrial oxidative stress. Thus, the primary function of this review, and indeed its novel feature, is to highlight the potential roles of mitochondria-targeted antioxidants on perturbations to mitochondrial oxidative stress and the implications for exercise, with special focus on mtDNA damage. A brief synopsis of the current literature addressing the sources of mitochondrial superoxide and hydrogen peroxide, and available mitochondria-targeted antioxidants is also discussed.

scholarly journals OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION

2020 ◽  
Vol 2 (338) ◽  
pp. 31-40
Author(s):  
B. A. Ussipbek ◽  
L. C. López ◽  
N. T. Ablaikhanova ◽  
M. K. Murzakhmetova
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Mitochondrial Dysfunction ◽  
Coenzyme Q10 ◽  
Mammalian Cells ◽  
Cell Damage ◽  
Coenzyme Q ◽  
Critical Role ◽  
Sulfide Oxidation ◽  
Mitochondrial Diseases

The process of cell damage resulting from the action of free radicals – reactive oxygen species (ROS) – is called oxidative stress. Most ROS are constantly formed in the cell – about 5 % of the oxygen consumed by tissues is converted into free radicals, but their level is normally so small that the cell inactivates them with the help of an antioxidant system. Different organs and tissues are exposed to different degrees of ROS and demonstrate different stability during the implementation of oxidative stress. The mechanisms of ROS formation by mitochondria under oxidative stress are still unclear. At the same time, it was found that mitochondrial dysfunction and the accumulation of mitochondrial mutations in tissues make a significant contribution to the aging process, as well as to the pathogenesis of a number of diseases characterized by neurodegeneration. Mutations lead to increased generation of free radicals, reduced ATP levels, and energy failure of cells. Coenzyme Q10 is a component of the mitochondrial respiratory chain. Violation of the biosynthesis of coenzyme Q10 can lead to a number of mitochondrial diseases. When coenzyme Q10 is deficient, sulfide metabolism plays a critical role. Sulfide metabolism in mammalian cells includes trans-sulfuration (biosynthetic) and hydrogen sulfide oxidation (H2S) (catabolic). Violation of H2S oxidation may contribute to oxidative stress in coenzyme Q deficiency or may play a synergistic role with oxidative stress in the pathogenesis of tissue specificity in coenzyme Q deficiency.

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