BACKGROUND: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-alpha (Ppar alpha), peroxisome proliferator-activated receptor-delta (Ppar delta), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. CONCLUSIONS/SIGNIFICANCE: These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain.

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats. Exercise training, consisting of treadmill running at 60% of the initial VO2max, reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass (SDH, citrate synthase, COX4, mtDNA), SIRT1 activity, AMPK, pAMPK and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), UCP3 and the Lon protease. Exercise training also decreased the gap between young and old animals in other measured parameters including NRF1, TFAM, Fis1, Mfn1 and polynucleotide phosphorylase (PNPase) levels. We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca(2+) homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca(2+) regulation is bidirectional, depending on the excitability of cells. Under physiological K(+)/Ca(2+) levels, CBD caused a subtle rise in [Ca(2+)](i), whereas CBD reduced [Ca(2+)](i) and prevented Ca(2+) oscillations under high-excitability conditions (high K(+) or exposure to the K(+) channel antagonist 4AP). Regulation of [Ca(2+)](i) was not primarily mediated by interactions with ryanodine or IP(3) receptors of the endoplasmic reticulum. Instead, dual-calcium imaging experiments with a cytosolic (fura-2 AM) and a mitochondrial (Rhod-FF, AM) fluorophore implied that mitochondria act as sinks and sources for CBD's [Ca(2+)](i) regulation. Application of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and the mitochondrial Na(+)/Ca(2+) exchange inhibitor, CGP 37157, but not the mitochondrial permeability transition pore inhibitor cyclosporin A, prevented subsequent CBD-induced Ca(2+) responses. In established human neuroblastoma cell lines (SH-SY5Y) treated with mitochondrial toxins, CBD (0.1 and 1 microm) was neuroprotective against the uncoupler FCCP (53% protection), and modestly protective against hydrogen peroxide- (16%) and oligomycin- (15%) mediated cell death, a pattern also confirmed in cultured hippocampal neurons. Thus, under pathological conditions involving mitochondrial dysfunction and Ca(2+) dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca(2+) homeostasis.

Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity, however the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim trained (EX, 5 weeks) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I+II state 3 respiration and the respiratory control ratio (RCR, complex I+II state 3 respiration / complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity (CSA) and mitochondrial DNA content. Furthermore, compared to the SED mice, arteries from EX mice displayed elevated transcript levels of PGC-1α (Ppargc1a) and the downstream targets Cox4i1, Idh2, Idh3a, increased MnSOD protein expression, increased endothelial NO synthase (eNOS) phosphorylation (Ser1177), and suppressed reactive oxygen species generation (all P<0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared to SED mice and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age and disease-related challenges to arterial function.

Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n=16-19/gr). EX mice performed 8 weeks of treadmill running for 1 hr/d, 6 d/wk at 25m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n=9-11/gr) were sacrificed and brain (brainstem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain), and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different sub-group of EX and SED mice (n=7-8/gr), performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1 and CS mRNA and mtDNA, in most brain regions in addition tothe soleus (P<0.05). Mean treadmill RTF increased from 74.0±9.6 min to 126.5±16.1 min following training (P<0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.

BACKGROUND: Considerable interest has been aroused in recent years by the well-known notion that biological systems are sensitive to visible light. With clinical applications of visible radiation in the far-red to near-infrared region of the spectrum in mind, we explored the effect of coherent red light irradiation with extremely low energy transfer on a neural cell line derived from rat pheochromocytoma. We focused on the effect of pulsed light laser irradiation vis-à-vis two distinct biological effects: neurite elongation under NGF stimulus on laminin-collagen substrate and cell viability during oxidative stress. METHODS: We used a 670 nm laser, with extremely low peak power output (3 mW/cm2) and at an extremely low dose (0.45 mJ/cm2). Neurite elongation wasmeasured over three days in culture. The effect of coherent red light irradiation on cell reaction to oxidative stress was evaluated through live-recording of mitochondria membrane potential (MMP) using JC1 vital dye and laser-confocal microscopy, in the absence (photo bleaching) and in the presence(oxidative stress) of H2O2, and by means of the MTT cell viability assay. RESULTS: We found that laser irradiation stimulates NGF-induced neurite elongation on a laminin-collagen coated substrate and protects PC12 cells against oxidative stress. CONCLUSION: These data suggest that red light radiation protects the viability of cell culture in case of oxidative stress, as indicated by MMP measurement and MTT assay. It also stimulates neurite outgrowth, and this effect could also have positive implications for axonal protection.

Beta amyloid (Aβ) is well accepted to play a central role in the pathogenesis of Alzheimer's disease (AD). The present work evaluated the therapeutic effects of low-level laser irradiation (LLI) on Aβ-induced neurotoxicity in rat hippocampus. Aβ 1-42 was injected bilaterally to the hippocampus CA1 region of adult male rats, and 2-minute daily LLI treatment was applied transcranially after Aβ injection for 5 consecutive days. LLI treatment suppressed Aβ-induced hippocampal neurodegeneration and long-term spatial and recognition memory impairments. Molecular studies revealed that LLI treatment: (1) restored mitochondrial dynamics, by altering fission and fusion protein levels thereby suppressing Aβ-induced extensive fragmentation; (2) suppressed Aβ-induced collapse of mitochondrial membrane potential; (3) reduced oxidized mitochondrial DNA and excessive mitophagy; (4) facilitated mitochondrial homeostasis via modulation of the Bcl-2-associated X protein/B-cell lymphoma 2 ratio and of mitochondrial antioxidant expression; (5) promoted cytochrome c oxidase activity and adenosine triphosphate synthesis; (6) suppressed Aβ-induced glucose-6-phosphate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activity; (7) enhanced the total antioxidant capacity of hippocampal CA1 neurons, whereas reduced the oxidative damage; and (8) suppressed Aβ-induced reactive gliosis, inflammation, and tau hyperphosphorylation. Although development of AD treatments has focused on reducingcerebral Aβ levels, by the time the clinical diagnosis of AD or mild cognitive impairment is made, the brain is likely to have already been exposed to years of elevated Aβ levels with dire consequences for multiple cellular pathways. By alleviating a broad spectrum of Aβ-induced pathology that includes mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal apoptosis, and tau pathology, LLI could represent a new promising therapeutic strategy for AD.

Mitochondria play a central role in the cell physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis and apoptosis control. Simultaneously mitochondria are the main producer and target of ROS and with the result, multiple mitochondrial diseases are related to ROS induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Among these, neurodegenerative diseases such as Alzheimer´s disease (AD), Parkinson´s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington´s disease (HD) and aging are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergeticfunction. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. Keeping these functions into consideration, this article was framed to review the protective role of melatonin with mechanistic insights against mitochondrial diseases, and may suggest the new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights have also been discussed.

Near-infrared light (NIL) promotes a wide range of biological effects including enhancement of energy production, gene expression and prevention of cell death. This is the first report of the in vivo neuroprotective effects of NIL against optic neuropathy induced by mitochondrial complex I inhibition. Subjects were pigmented rats that received single bilateral intravitreal doses of rotenone, a mitochondrial complex I inhibitor, or rotenone plus one of three different doses of NIL. Treatment effects were evaluated at behavioral, structural and neurochemical levels. Rotenone induced a decrease in visual function, as determined by changes in the dark-adapted illuminance sensitivity threshold, escape latency and rate of successful trials in a two-choice visual task, compared with vehicle-treated controls. Behavioral impairment correlated with a decrease in retinal and visual pathway metabolic activity, retinal nerve fiber layer thickness and ganglion cell layer cell density. These changes were prevented by NIL treatments in a dose-dependent manner. Whole-brain cytochrome oxidase and superoxide dismutase activities were also increased in NIL-treated subjects in a dose-dependent manner, suggesting an in vivo transcranial effect of NIL. In whole-brain membrane isolates, NIL prevented the rotenone-induced decrease in cell respiration. The results show that NIL treatment can effectively prevent the neurotoxic effects of rotenone and that it might be used in the treatment of neurodegenerative disorders associated with mitochondrial dysfunction.

While beneficial properties of physical activity and exercise on human health have been extensively reported in literature, the exact mechanism(s) underpinning impacts of exercise are not well understood. Focusing on metabolic disorders, as the main causes of social and economic burden in current century, exercise exhibited promising effects in prevention, alleviation and retardation of these disorders including, type 2 diabetes (T2D), Alzheimer's disease (AD), major depressive disorder (MDD) and obesity. Recent evidence has unmasked the role of mitochondrial dysfunction and chronic inflammation in pathophysiology of these disorders. Despite of the wealth of research on the etiology of metabolic disorders, intimate connections between these diseases, complex pathophysiology and their comorbidity still remains a challenging dilemma. In addition, although physical activity has improving effects on human health, it is not clear that how exercise is able to exert its modulatory effects on outcomes of metabolic disorders. Among several mechanisms, we assumed the hypothesis that exercise mitigates the production of mitochondrial-induced reactive oxygen species (ROS) and danger associated molecular patterns (DAMPs) as the main triggering factors for inflammasome formation. Since inflammasomes are of highly deleterious molecules relevant to pathogenesis of metabolic disorders, we hypothesized that beneficial effects of exercise may be associated with its ability to enhance the mitochondrial biogenesis and glucose transportation through generation of brain derived neurotrophic factor (BDNF). Also, we proposed that boosting impact of exercise on autophagy process accelerates the elimination of damaged mitochondria and thus, results in considerable decrease in production of ROS and DAMPs and consequently sterile inflammation.

The study was designed to investigate the beneficial effect of quercetin supplementation in 3-nitropropionic acid (3-NP) induced model of Huntington's disease (HD). HD was induced in rats by administering sub-chronic dose of 3-NP, intraperitoneally, twice daily for 17days. Quercetin was supplemented at a dose of 25mg/kg body weight by oral gavage for 21days. At the end of treatment, mitochondrial bioenergetics, mitochondrial swelling, oxidative stress, neurobehavioral deficits and histopathological changes were analyzed. Quercetin supplementation was able to reverse 3-NP induced inhibition of respiratory chain complexes, restore ATP levels, attenuate mitochondrial oxidative stress in terms of lipid peroxidation and prevent mitochondrial swelling. Quercetin administration also restored the activities of superoxide dismutase and catalase along with thiol content in 3-NP treated animals. Beneficial effect of quercetin administration was observed on 3-NP induced motor deficits analyzed by narrow beam walk and footprint analysis. Histopathological analysis of 3-NP treated rats revealed pyknotic nuclei and astrogliosis in striatum, which were reduced or absent in quercetin supplemented animals. Altogether, our results show that quercetin supplementation to 3-NP induced HD animals ameliorated mitochondrial dysfunctions, oxidative stress and neurobehavioral deficits in rats showing potential of this flavonoid in maintaining mitochondrial functions, suggesting a putative role of quercetin in HD management.

It has been known for more than 4 decades that exercise causes increases in skeletal muscle mitochondrial enzyme content and activity (i.e., mitochondrial biogenesis). Increasing evidence now suggests that exercise can induce mitochondrial biogenesis in a wide range of tissues not normally associated with the metabolic demands of exercise. Perturbations in mitochondrial content and (or) function have been linked to a wide variety of diseases, in multiple tissues, and exercise may serve as a potent approach by which to prevent and (or) treat these pathologies. In this context, the purpose of this review is to highlight the effects of exercise, and the underlying mechanisms therein, on the induction of mitochondrial biogenesis in skeletal muscle, adipose tissue, liver, brain, and kidney.