stilbenes and mitoquinone

Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins, occurs most frequently and originates from mutations in either the nuclear DNA, encoding 38 structural subunits and several assembly factors, or the mitochondrial DNA, encoding 7 structural subunits. The deficiency is associated with devastating multisystemic disorders, often affecting the brain, with onset in early childhood. There are currently no rational treatment strategies. Here, we present an overview of the genetic origins and cellular consequences of this deficiency and discuss how these insights might aid future development of treatment strategies.

Topics: Antioxidants; Child; Child, Preschool; Developmental Disabilities; Disease Progression; Drug Delivery Systems; Electron Transport Complex I; Energy Metabolism; Humans; Infant; Infant, Newborn; Mitochondrial Diseases; Organophosphorus Compounds; Oxidative Phosphorylation; Plastoquinone; Resveratrol; Stilbenes; Ubiquinone

The dynamic regulation of the structure, function and turnover of mitochondria is recognized as an immutable control node maintaining cellular integrity and homeostasis. The term 'mitohormesis' has recently been coined to describe the adaptive reprogramming of mitochondrial biology in response to low levels of metabolic substrate deprivation to augment subsequent mitochondrial and cellular tolerance to biological stress. Disruption of these regulatory programs gives rise to cardiovascular and neurodegenerative diseases, and augmentation or fine-tuning of these programs may ameliorate mitochondrial and global cellular stress tolerance. This is in part via the regulation of reactive oxygen species, calcium homeostasis, and in response to caloric restriction, the capacity to augment DNA repair. The objective of this manuscript is to briefly review these regulatory programs and to postulate novel therapeutic approaches with the primary goal of modulating mitochondria to enhance tolerance to cardiac ischemic stress.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Drug Delivery Systems; Homeostasis; Humans; Ischemic Preconditioning; Mitochondria; Multienzyme Complexes; Myocardial Reperfusion Injury; Nitrites; Organophosphorus Compounds; Protein Serine-Threonine Kinases; Resveratrol; Stilbenes; Ubiquinone

Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA.

Topics: Administration, Oral; Amino Acids, Branched-Chain; Animals; Antioxidants; Disease Models, Animal; Heart; Humans; Lipid Peroxidation; Mice; Organophosphorus Compounds; Oxidative Stress; Propionic Acidemia; Resveratrol; Stilbenes; Ubiquinone

Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin dependent enzyme propionyl-CoA carboxylase (PCC) is one of the most frequent organic acidurias in humans. Most PA patients present in the neonatal period with metabolic acidosis and hyperammonemia, developing different neurological symptoms, movement disorders and cardiac complications. There is strong evidence indicating that oxidative damage could be a pathogenic factor in neurodegenerative, mitochondrial and metabolic diseases. Recently, we identified an increase in ROS levels in PA patients-derived fibroblasts. Here, we analyze the capability of seven antioxidants to scavenge ROS production in PA patients' cells. Tiron, trolox, resveratrol and MitoQ significantly reduced ROS content in patients and controls' fibroblasts. In addition, changes in the expression of two antioxidant enzymes, superoxide dismutase and glutathione peroxidase, were observed in PA patients-derived fibroblasts after tiron and resveratrol treatment. Our results in PA cellular models establish the proof of concept of the potential of antioxidants as an adjuvant therapy for PA and pave the way for future assessment of antioxidant strategies in the murine model of PA.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Antioxidants; Chromans; Fibroblasts; Gene Expression; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Humans; Methylmalonyl-CoA Decarboxylase; Mitochondria; Mutation; Organophosphorus Compounds; Primary Cell Culture; Propionic Acidemia; Reactive Oxygen Species; Resveratrol; Stilbenes; Superoxide Dismutase; Ubiquinone

Mitochondrial reactive oxygen species (ROS) have been demonstrated to play an important role as signaling and regulating molecules in human adipocytes. In order to evaluate the differential modulating roles of antioxidants, we treated human adipocytes differentiated from human bone marrow-derived mesenchymal stem cells with MitoQ, resveratrol and curcumin. The effects on ROS, viability, mitochondrial respiration and intracellular ATP levels were examined. MitoQ lowered both oxidizing and reducing ROS. Resveratrol decreased reducing and curcumin oxidizing radicals only. All three substances slightly decreased state III respiration immediately after addition. After 24 h of treatment, MitoQ inhibited both basal and uncoupled oxygen consumption, whereas curcumin and resveratrol had no effect. Intracellular ATP levels were not altered. This demonstrates that MitoQ, resveratrol and curcumin exert potent modulating effects on ROS signaling in human adipocyte with marginal effects on metabolic parameters.

Topics: Adipocytes; Antioxidants; Bone Marrow Cells; Cell Differentiation; Cell Respiration; Curcumin; Humans; Hydrogen Peroxide; Mesenchymal Stem Cells; Mitochondria; Organophosphorus Compounds; Oxygen Consumption; Reactive Oxygen Species; Resveratrol; Stilbenes; Ubiquinone