stilbenes and Mitochondrial-Diseases

In human cells, mitochondria provide the largest part of cellular energy in the form of adenosine triphosphate generated by the process of oxidative phosphorylation (OXPHOS). Impaired OXPHOS activity leads to a heterogeneous group of inherited diseases for which therapeutic options today remain very limited. Potential innovative strategies aim to ameliorate mitochondrial function by increasing the total mitochondrial load of tissues and/or to scavenge the excess of reactive oxygen species generated by OXPHOS malfunctioning. In this respect, resveratrol, a compound that conveniently combines mitogenetic with antioxidant activities and, as a bonus, possesses anti-apoptotic properties, has come forward as a promising nutraceutical. We review the scientific evidence gathered so far through experiments in both in vitro and in vivo systems, evaluating the therapeutic effect that resveratrol is expected to generate in mitochondrial patients. The obtained results are encouraging, but clearly show that achieving normalization of OXPHOS function with this strategy alone could prove to be an unattainable goal.

Topics: Adenosine Triphosphate; Apoptosis; Dietary Supplements; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation; Reactive Oxygen Species; Resveratrol; Stilbenes

The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to up-regulate mitochondrial biogenesis, in order to increase the residual OXPHOS activity present in affected animals and thereby to ameliorate the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of preclinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Bezafibrate; Disease Models, Animal; Energy Metabolism; Mitochondria; Mitochondrial Diseases; Mitochondrial Turnover; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Ribonucleotides; Sirtuin 1; Stilbenes; Transcription Factors; Up-Regulation

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

Evidence from animal models and preliminary studies in humans indicates that calorie restriction (CR) delays cardiac aging and can prevent cardiovascular disease. These effects are mediated by a wide spectrum of biochemical and cellular adaptations, including redox homeostasis, mitochondrial function, inflammation, apoptosis, and autophagy. Despite the beneficial effects of CR, its large-scale implementation is challenged by applicability issues as well as health concerns. However, preclinical studies indicate that specific compounds, such as resveratrol, may mimic many of the effects of CR, thus potentially obviating the need for drastic food intake reductions. Results from ongoing clinical trials will reveal whether the intriguing alternative of CR mimetics represents a safe and effective strategy to promote cardiovascular health and delay cardiac aging in humans.

Topics: Aged; Animals; Antioxidants; Apoptosis; Autophagy; Caloric Restriction; Cardiovascular Diseases; Disease Models, Animal; Forecasting; Heart Diseases; Homeostasis; Humans; Inflammation; Inflammation Mediators; Mitochondria, Heart; Mitochondrial Diseases; Obesity; Oxidation-Reduction; Oxidative Stress; Resveratrol; Stilbenes

This study investigated the potential of resveratrol (RSV) and its derivative pterostilbene (PT) to prevent diquat (DQ)-induced hepatic oxidative damage and mitochondrial dysfunction in piglets. Seventy-two weanling piglets were randomly divided into the following treatment groups: non-challenged control group, DQ-challenged control group, and DQ-challenged groups supplemented with either 300 mg RSV per kg of diet or an equivalent amount of PT. Each treatment group consisted of six replicates with three piglets per replicate (n = 6). After a two-week feeding trial, piglets were intraperitoneally injected with either 10 mg DQ per kg of body weight or sterile saline. At 24 hours post-injection, one piglet from each replicate (six piglets per treatment) was randomly selected for sample collection and biochemical analysis. Compared with the DQ-challenged control group, PT attenuated the growth loss of piglets after the DQ challenge (P < 0.05). Administration of PT was more effective than its parent compound in inhibiting the DQ-induced hepatic apoptosis and the increased generation of total cholesterol, superoxide anion, and lipid peroxidation products (P < 0.05). Specifically, PT facilitated nuclear factor erythroid 2-related factor 2 signals and the expression and activity of manganese superoxide dismutase, while it also prevented mitochondrial swelling, membrane potential collapse, and adenosine triphosphate depletion, possibly through the activation of sirtuin 1 (P < 0.05). These results indicate that PT may be superior to RSV as an antioxidant to protect the liver of young piglets from oxidative insults.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Diquat; Energy Metabolism; Gene Expression Regulation; Glutathione; Herbicides; Liver; Male; Mitochondrial Diseases; NF-E2-Related Factor 2; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Superoxides; Swine

To explore the roles of mitochondrial biogenesis and dynamics in both RGC-5 cells apoptosis and rat retinal damage induced by elevated pressure and their involvement in resveratrol (RSV)-induced cell protection.. The chronic ocular hypertension (COH) model was established in rats by injecting superparamagnetic iron oxide into anterior chamber. The RGC-5 cells were incubated under ambient and elevated pressure (70 mm Hg) respectively. The intraocular pressure (IOP) was measured using a handheld Tonolab tonometer; mitochondrial dysfunction was analyzed by membrane potential (MMP) depolarization, reactive oxygen species (ROS) level and transmission electron microscope (TEM) detection. Annexin V/PI staining and the terminal deoxynucleotidy transferase dUTP nick end labeling (TUNEL) staining assay were performed for apoptosis detection. Hematoxylin-Eosin staining was performed for retinal morphology detection. The expression of mitochondrial biogenesis and dynamics relating proteins were analyzed by western blot.. The retinal morphology and mitochondrial function deteriorated in chronic ocular hypertension (COH) rats. The cells showed apoptosis and mitochondrial dysfunction under elevated pressure (70 mm Hg) incubation. Upregulating AMPK, NRF-1, Tfam, mfn-2, OPA1 expression with RSV-treatment could decrease the cell apoptosis, mitochondrial membrane potential depolarization, ROS generation both in in vitro and in vivo experiments, and normalized the retinal morphology in vivo.. Both in vitro and in vivo experiments demonstrated that activated AMPK/PGC-1α signaling pathway and improved expression of proteins were related to mitochondrial dynamics could be the possible mechanism underlying in the RSV's mitochondrial protection.

Topics: Animals; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Survival; Intraocular Pressure; Male; Mitochondria; Mitochondrial Diseases; Ocular Hypertension; Organelle Biogenesis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Retina; Stilbenes

The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERRα). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD(+)-dependent deacetylase and is critically dependent on NAD(+) levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies.

Topics: Antioxidants; Cells, Cultured; Electron Transport Complex I; ERRalpha Estrogen-Related Receptor; Estrogen Receptor alpha; Fibroblasts; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Oxygen Consumption; Reactive Oxygen Species; Receptors, Estrogen; Resveratrol; Signal Transduction; Sirtuin 3; Stilbenes; Superoxide Dismutase

Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DN

Topics: Animals; DNA, Mitochondrial; Humans; Metformin; Mitochondria; Mitochondrial Diseases; Resveratrol; Stilbenes

The beneficial effects of dietary polyphenols on health are due not only to their antioxidant properties but also to their antibacterial, anti-inflammatory and/or anti-tumoral activities. It has recently been proposed that protection of mitochondrial function (which is altered in several diseases such as Alzheimer, Parkinson, obesity and diabetes) by these compounds, may be important in explaining the beneficial effects of polyphenols on health. The aim of this study was to evaluate the protective effects of dietary polyphenols quercetin, rutin, resveratrol and epigallocatechin gallate against the alterations of mitochondrial function induced by indomethacin (INDO) in intestinal epithelial Caco-2 cells, and to address the mechanism involved in such damaging effect by INDO, which generates oxidative stress. INDO concentration dependently decreases cellular ATP levels and mitochondrial membrane potential in Caco-2 cells after 20min of incubation. INDO also inhibits the activity of mitochondrial complex I and causes accumulation of NADH; leading to overproduction of mitochondrial O(2)()(-), since it is prevented by pyruvate. Quercetin (0.01mg/ml), resveratrol (0.1mg/ml) and rutin (1mg/ml) protected Caco-2 cells against INDO-induced mitochondrial dysfunction, while no protection was observed with epigallocatechin gallate. Quercetin was the most efficient in protecting against mitochondrial dysfunction; this could be due to its ability to enter cells and accumulate in mitochondria. Additionally its structural similarity with rotenone could favor its binding to the ubiquinone site of complex I, protecting it from inhibitors such as INDO or rotenone. These findings suggest a possible new protective role for dietary polyphenols for mitochondria, complementary of their antioxidant property. This new role might expand the preventive and/or therapeutic use of PPs in conditions involving mitochondrial dysfunction and associated with increased oxidative stress at the cellular or tissue levels.

Topics: Adenosine Triphosphate; Caco-2 Cells; Catechin; Drug Interactions; Electron Transport Complex I; Gastrointestinal Diseases; Humans; Indomethacin; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Quercetin; Resveratrol; Rutin; Stilbenes; Superoxides

The main objective of this study was to investigate the activity of polydatin on mitochondrial dysfunction and lysosomal stability of arteriolar smooth muscle cells (ASMCs) in severe shock. The experimental animals (rats) were divided into five groups: control, hemorrhagic shock, shock + CsA, shock + Res, and shock + PD (exposed to cyclosporin A, resveratrol, or polydatin following induction of hemorrhagic shock, respectively). The calcein-Co(2+) technique revealed opening of ASMC mitochondrial permeability transition pores (mPTP) after shock with resulting mitochondrial swelling, decreased mitochondrial membrane potential (ΔΨm), and reduced intracellular ATP levels. These alterations were all inhibited by exposure to PD, which was significantly more effective than CsA and Res. PD also preserved lysosomal stability, suppressed activation of K(ATP) channels, ASMC hyperpolarization, and reduced vasoresponsiveness to norepinephrine that normally follows severe shock. The results demonstrate that exposure to PD after initiation of severe shock effectively preserves ASMC mitochondrial integrity and has a significant therapeutic effect in severe shock. The effects may partially result from lysosomal stabilization against shock-induced oxidative stress and depressed relocation of hydrolytic enzymes and redox-active lysosomal iron that, in turn, may induce mPTP opening.

Topics: Adenosine Triphosphate; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Cyclosporine; Cytoprotection; Glucosides; KATP Channels; Lysosomes; Membrane Potential, Mitochondrial; Mitochondria, Muscle; Mitochondrial Diseases; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocytes, Smooth Muscle; Norepinephrine; Rats; Resveratrol; Shock, Hemorrhagic; Stilbenes

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Gene Expression Regulation; Green Fluorescent Proteins; Hyperalgesia; Male; Membrane Potentials; Mice; Mitochondrial Diseases; Mitochondrial Membranes; Mutation; Nerve Fibers, Myelinated; Neurites; Oxygen Consumption; Patch-Clamp Techniques; Peripheral Nervous System Diseases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reaction Time; Resveratrol; RNA-Binding Proteins; Sensory Receptor Cells; Signal Transduction; Stilbenes; Transcription Factors; Transduction, Genetic