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Various roles of intestinal flora in the gut-brain axis response pathway have received enormous attention because of their unique position in intestinal flora-derived metabolites regulating hormones, inducing appetite, and modulating energy metabolism. Reward pathways in the brain play a crucial role in gut-brain communications, but the mechanisms have not been methodically understood. This review outlined the mechanisms by which leptin, ghrelin, and insulin are influenced by intestinal flora-derived metabolites to regulate appetite and body weight, focused on the significance of the paraventricular nucleus and ventromedial prefrontal cortex in food reward. The vagus nerve and mitochondria are essential pathways of the intestinal flora involved in the modulation of neurotransmitters, neural signaling, and neurotransmission in gut-brain communications. The dynamic response to nutrient intake and changes in the characteristics of feeding activity requires the participation of the vagus nerve to transmit messages to be completed. SCFAs, Bas, BCAAs, and induced hormones mediate the sensory information and reward signaling of the host in the complex regulatory mechanism of food selection, and the composition of the intestinal flora significantly impacts this process. Food reward in the process of obesity based on gut-brain communications expands new ideas for the prevention and treatment of obesity. [ABSTRACT FROM AUTHOR]

Abstract Background Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. Methods Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. Results mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. Limitations The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. Conclusions The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

Background: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. Methods: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. Results: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. Limitations: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. Conclusions: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212–2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212–2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212–2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling. [ABSTRACT FROM AUTHOR]

Little is known about the effects of statins, which are cholesterol-lowering drugs, on the bioenergetic functions of mitochondria in the brain. This study aimed to elucidate the direct effects of atorvastatin and simvastatin on the bioenergetics of isolated rat brain mitochondria by measuring the statin-induced changes in respiratory chain activity, ATP synthesis efficiency, and the production of reactive oxygen species (ROS). Our results in isolated brain mitochondria are the first to demonstrate that atorvastatin and simvastatin dose-dependently significantly inhibit the activity of the mitochondrial respiratory chain, resulting in a decreased respiratory rate, a decreased membrane potential, and increased ROS formation. Moreover, the tested statins reduced mitochondrial coupling parameters, the ADP/O ratio, the respiratory control ratio, and thus, the oxidative phosphorylation efficiency in brain mitochondria. Among the oxidative phosphorylation complexes, statin-induced mitochondrial impairment concerned complex I, complex III, and ATP synthase activity. The calcium-containing atorvastatin had a significantly more substantial effect on isolated brain mitochondria than simvastatin. The higher inhibitory effect of atorvastatin was dependent on calcium ions, which may lead to the disruption of calcium homeostasis in mitochondria. These findings suggest that while statins are effective in their primary role as cholesterol-lowering agents, their use may impair mitochondrial function, which may have consequences for brain health, particularly when mitochondrial energy efficiency is critical. [ABSTRACT FROM AUTHOR]

Astragalus glycyphyllos (Fabaceae) is used in the traditional medicine of many countries against hepatic and cardiac disorders. The plant contains mainly flavonoids and saponins. From a defatted methanol extract from its overground parts, a new triterpenoid saponin, 3-O-[α-L-rhamnopyranosyl-(1→2)]-β-D-xylopyranosyl]-24-O-α-L-arabinopyranosyl-3β,6α,16β,24(R),25-pentahydroxy-20R-cycloartane, together with the rare saponin astrachrysoside A, were isolated using various chromatography methods. The compounds were identified via extensive high resolution electrospray ionisation mass spectrometry (HRESIMS) and NMR analyses. Both saponins were examined for their possible antioxidant and neuroprotective activity in three different in vitro models. Rat brain synaptosomes, mitochondria, and microsomes were isolated via centrifugation using Percoll gradient. They were treated with the compounds in three different concentrations alone, and in combination with 6-hydroxydopamine or tert-butyl hydroperoxide as toxic agents. It was found that the compounds had statistically significant dose-dependent in vitro protective activity on the sub-cellular fractions. The compounds exhibited a weak inhibitory effect on the enzyme activity of human recombinant monoamine oxidase type B (hMAO-B), compared to selegiline. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia that affects practically all tissues and organs, being the brain one of most susceptible, due to overproduction of reactive oxygen species induced by diabetes. Eryngium carlinae is a plant used in traditional Mexican medicine to treat diabetes, which has already been experimentally shown have hypoglycemic, antioxidant and hypolipidemic properties. The green synthesis of nanoparticles is a technique that combines plant extracts with metallic nanoparticles, so that the nanoparticles reduce the absorption and distribution time of drugs or compounds, increasing their effectiveness. In this work, the antioxidant effects and mitochondrial function in the brain were evaluated, as well as the hypoglycemic and hypolipidemic effect in serum of both the aqueous extract of the aerial part of E. carlinae, as well as its combination with silver nanoparticles of green synthesis. Administration with both, extract and the combination significantly decreased the production of reactive oxygen species, lipid peroxidation, and restored the activity of superoxide dismutase 2, glutathione peroxidase, and electron transport chain complexes in brain, while that the extract-nanoparticle combination decreased blood glucose and triglyceride levels. The results obtained suggest that both treatments have oxidative activity and restore mitochondrial function in the brain of diabetic rats. [ABSTRACT FROM AUTHOR]

The study aimed to explore the role of age-associated elevated cytosolic Ca2+ in changes of brain mitochondria energetic processes. Two groups of rats, young adults (4 months) and advanced old (24 months), were evaluated for potential alterations of mitochondrial parameters, the oxidative phosphorylation (OxPhos), membrane potential, calcium retention capacity, activity of glutamate/aspartate carrier (aralar), and ROS formation. We demonstrated that the brain mitochondria of older animals have a lower resistance to Ca2+ stress with resulting consequences. The suppressed complex I OxPhos and decreased membrane potential were accompanied by reduction of the Ca2+ threshold required for induction of mPTP. The Ca2+ binding sites of mitochondrial aralar mediated a lower activity of old brain mitochondria. The altered interaction between aralar and mPTP may underlie mitochondrial dysregulation leading to energetic depression during aging. At the advanced stages of aging, the declined metabolism is accompanied by the diminished oxidative background. • Aged brain mitochondria intolerant to high cytosolic Ca2+content. • Complex I OxPhos, ΔΨ m , Ca2+ retention capacity, ROS formation decline upon aging. • Activity of mitochondrial aralar decreases during aging. [ABSTRACT FROM AUTHOR]

We present evidence that metabolic syndrome (MetS) represents the postreproductive stage of the human postembryonic ontogenesis. Accordingly, the genes governing this stage experience relatively weak evolutionary selection pressure, thus representing the metabolic phenotype of distant ancestors with β-oxidation of long-chain fatty acids (FAs) as the primary energy source. Mitochondria oxidize at high-rate FAs only when succinate, glutamate, or pyruvate are present. The heart and brain mitochondria work at a wide range of functional loads and possess an intrinsic inhibition of complex II to prevent oxidative stress at periods of low functional activity. Kidney mitochondria constantly work at a high rate and lack inhibition of complex II. We suggest that in people with MetS, oxidative stress is the central mechanism of the heart and brain pathologies. Oxidative stress is a secondary pathogenetic mechanism in the kidney, while the primary mechanisms are kidney hypoxia caused by persistent hyperglycemia and hypertension. Current evidence suggests that most of the nongenetic pathologies associated with MetS originate from the inconsistencies between the metabolic phenotype acquired after the transition to the postreproductive stage and excessive consumption of food rich in carbohydrates and a sedentary lifestyle. [ABSTRACT FROM AUTHOR]

Hypothermia provides an effective neuro and cardio-protection in clinical settings implying ischemia/reperfusion injury (I/R). At the onset of reperfusion, succinate-induced reactive oxygen species (ROS) production, impaired oxidative phosphorylation (OXPHOS), and decreased Ca2+ retention capacity (CRC) concur to mitochondrial damages. We explored the effects of temperature from 6 to 37 °C on OXPHOS, ROS production, and CRC, using isolated mitochondria from mouse brain and heart. Oxygen consumption and ROS production was gradually inhibited when cooling from 37 to 6 °C in brain mitochondria (BM) and heart mitochondria (HM). The decrease in ROS production was gradual in BM but steeper between 31 and 20 °C in HM. In respiring mitochondria, the gradual activation of complex II, in addition of complex I, dramatically enhanced ROS production at all temperatures without modifying respiration, likely because of ubiquinone over-reduction. Finally, CRC values were linearly increased by cooling in both BM and HM. In BM, the Ca2+ uptake rate by the mitochondrial calcium uniporter (MCU) decreased by 2.7-fold between 25 and 37 °C, but decreased by 5.7-fold between 25 and 37 °C in HM. In conclusion, mild cold (25–37 °C) exerts differential inhibitory effects by preventing ROS production, by reverse electron transfer (RET) in BM, and by reducing MCU-mediated Ca2+ uptake rate in BM and HM. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether continuous IV infusion of molar sodium lactate would limit cardiac arrest-induced neurologic injury and cardiovascular failure.Design: Randomized blinded study (animal model).Setting: University animal research facility.Subjects: Twenty-four adult male "New Zealand White" rabbits.Interventions: Anesthetized rabbits underwent 12.5 minutes of asphyxial cardiac arrest and were randomized to receive either normal saline (control group, n = 12) or molar sodium lactate (molar sodium lactate group, n = 12) at a rate of 5 mL/kg/hr during the whole 120-minute reperfusion period.Measurements and Main Results: Pupillary reactivity (primary outcome), levels of S100β protein, in vitro brain mitochondria functions, cardiovascular function, and fluid balance were assessed. Molar sodium lactate reduced brain injury, with a higher proportion of animals exhibiting pupillary reactivity to light (83% vs 25% in the CTRL group, p = 0.01) and lower S100β protein levels (189 ± 42 vs 412 ± 63 pg/mL, p < 0.01) at the end of the protocol. Molar sodium lactate significantly prevented cardiac arrest-induced decrease in oxidative phosphorylation and mitochondrial calcium-retention capacity compared with controls. At 120 minutes of reperfusion, survival did not significantly differ between the groups (10/12, 83% in the molar sodium lactate group vs nine of 12, 75% in the control group; p > 0.99), but hemodynamics were significantly improved in the molar sodium lactate group compared with the control group (higher mean arterial pressure [49 ± 2 vs 29 ± 3 mm Hg; p < 0.05], higher cardiac output [108 ± 4 vs 58 ± 9 mL/min; p < 0.05], higher left ventricle surface shortening fraction [38% ± 3% vs 19% ± 3%; p < 0.05], and lower left ventricular end-diastolic pressure [3 ± 1 vs 8 ± 2 mm Hg; p < 0.01]). While fluid intake was similar in both groups, fluid balance was higher in control animals (11 ± 1 mL/kg) than that in molar sodium lactate-treated rabbits (1 ± 3 mL/kg; p < 0.01) due to lower diuresis.Conclusions: Molar sodium lactate was effective in limiting the severity of the postcardiac arrest syndrome. This preclinical study opens up new perspectives for the treatment of cardiac arrest. [ABSTRACT FROM AUTHOR]

Mitochondria play an essential role in maintaining intraneuronal calcium homeostasis. Mitochondrial calcium uniporter (MCU) is a determined major brain mitochondrial calcium entry pathway. Activated MCU-mediated mitochondrial calcium overloading has been linked with brain mitochondrial pathology in disease conditions. Cyclophilin D (CypD)-mediated mitochondrial permeability transition (mPT) favors mitochondrial calcium efflux. The physiological function of CypD-mediated mPT has received increasing recognition. However, the regulatory role of CypD-mediated mPT in brain mitochondrial calcium dynamics in response to mitochondrial calcium accumulation via MCU has not been comprehensively studied. Here, by adopting purified brain mitochondria, we have determined an effect of CypD and CypD-mediated mPT against mitochondrial calcium overloading. In addition, blockade of CypD pharmaceutically or genetically blunts brain mitochondrial MCU's sensitivity to its inhibitor. Therefore, our findings suggest that CypD-mediated mPT is a mitochondrial compensatory response to MCU-mediated excess mitochondrial calcium accumulation. Moreover, CypD may potentially modulate MCU function in calcium-stressed mitochondria. • MCU is the main entrance for calcium influx in brain mitochondria. • CypD-mediated mPT can counterbalance mitochondrial calcium overloading. • CypD-mediated mPT is a mitochondrial compensatory response to MCU-mediated excess mitochondrial calcium accumulation. [ABSTRACT FROM AUTHOR]

Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the brain toxicity following the respiratory contact with multi-wall carbon nanotubes (MWCNTs) in male Wistar rats. Rats were exposed to 5 mg/m3 MWCNT aerosol in different sizes and purities for 5 h/day, 5 days/week for 2 weeks in a whole-body exposure chamber. After 2-week exposure, mitochondrial isolation was performed from different parts of rat brain (hippocampus, frontal cortex, and cerebellum) and parameters of mitochondrial toxicity including mitochondrial succinate dehydrogenase (SDH) activity, generation of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release, ATP level, mitochondrial GSH, and lipid peroxidation were evaluated. Our results demonstrated that MWCNTs with different characteristics, in size and purity, significantly (P < 0.05) decreased SDH activity, GSH, and ATP level, and increased mitochondrial ROS production, lipid peroxidation, mitochondrial swelling, MMP collapse, and cytochrome c release in the brain mitochondria. In conclusion, we suggested that MWCNTs with different characteristics, in size and purity, induce damage in varying degrees on the mitochondrial respiratory chain and increase mitochondrial ROS formation in different parts of rat brain (hippocampus, frontal cortex, and cerebellum). [ABSTRACT FROM AUTHOR]

Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3–P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3–P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

The glutathione system in the mitochondria of the brain plays an important role in maintaining the redox balance and thiol–disulfide homeostasis, whose violations are the important component of the biochemical shifts in neurodegenerative diseases. Mitochondrial dysfunction is known to be accompanied by the activation of free radical processes, changes in energy metabolism, and is involved in the induction of apoptotic signals. The formation of disulfide bonds is a leading factor in the folding and maintenance of the three-dimensional conformation of many specific proteins that selectively accumulate in brain structures during neurodegenerative pathology. In this study, we estimated brain mitochondria redox status and functioning during induction of oxidative damage in vitro. We have shown that the development of oxidative stress in vitro is accompanied by inhibition of energy metabolism in the brain mitochondria, a shift in the redox potential of the glutathione system to the oxidized side, and activation of S-glutathionylation of proteins. Moreover, we studied the effects of pantothenic acid derivatives—precursors of coenzyme A (CoA), primarily D-panthenol, that exhibit high neuroprotective activity in experimental models of neurodegeneration. Panthenol contributes to the significant restoration of the activity of enzymes of mitochondrial energy metabolism, normalization of the redox potential of the glutathione system, and a decrease in the level of S-glutathionylated proteins in brain mitochondria. The addition of succinate and glutathione precursor N-acetylcysteine enhances the protective effects of the drug.

The review summarizes the data of our research and published studies on the ubiquitination of brain mitochondrial proteins and its changes during the development of experimental parkinsonism and administration of the neuroprotector isatin (indole-2,3-dione) with special attention to the mitochondrial ubiquitin-conjugating system and location of ubiquitinated proteins in these organelles. Incubation of brain mitochondrial fraction with biotinylated ubiquitin in vitro resulted in the incorporation of biotinylated ubiquitin in both mitochondrial and mitochondria-associated proteins. According to the interactome analysis, the identified non-ubiquitinated proteins are able to form tight complexes with ubiquitinated proteins or their partners and components of mitochondrial membranes, in which interactions of ubiquitin chains with the ubiquitin-binding protein domains play an important role. The studies of endogenous ubiquitination in the total brain mitochondrial fraction of C57Bl mice performed in different laboratories have shown that mitochondrial proteins represent about 30% of all ubiquitinated proteins. However, comparison of brain subproteomes of mitochondrial ubiquitinated proteins reported in the literature revealed significant differences both in their composition and involvement of identified ubiquitinated proteins in biological processes listed in the Gene Ontology database. The development of experimental parkinsonism in C57Bl mice induced by a single-dose administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in a decrease in the total number of mitochondrial ubiquitinated proteins and increase in the number of oxidized mitochondrial proteins containing the ubiquitin signature (K-ε-GG). Comparison of ubiquitinated proteins associated with the mouse brain mitochondrial fraction and mouse brain mitochondrial proteins bound to the proteasome ubiquitin receptor (Rpn10 subunit) did not reveal any common proteins. This suggests that ubiquitination of brain mitochondrial proteins is not directly related to their degradation in the proteasomes. Proteomic profiling of brain isatin-binding proteins identified enzymes involved in the ubiquitin-conjugating system functioning. Mapping of the identified isatin-binding proteins to known metabolic pathways indicates their participation in the parkin (E3 ubiquitin ligase)-associated pathway (CH000000947). The functional links involving brain mitochondrial ubiquitinated proteins were found only in the group of animals with the MPTP-induced parkinsonism, but not in animals treated with MPTP/isatin or isatin only. This suggests that the neuroprotective effect of isatin may be associated with the impaired functional relationships of proteins targeted to subsequent degradation. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction named complex I syndrome was observed in striatum mitochondria of rotenone treated rats (2 mg rotenone/kg, i. p., for 30 or 60 days) in an animal model of Parkinson disease. After 60 days of rotenone treatment, the animals showed: (a) 6-fold increased bradykinesia and 60% decreased locomotor activity; (b) 35-34% decreases in striatum O 2 uptake and in state 3 mitochondrial respiration with malate-glutamate as substrate; (c) 43–57% diminished striatum complex I activity with 60–71% decreased striatum mitochondrial NOS activity, determined both as biochemical activity and as functional activity (by the NO inhibition of active respiration); (d) 34–40% increased rates of mitochondrial O 2 •- and H 2 O 2 productions and 36–46% increased contents of the products of phospholipid peroxidation and of protein oxidation; and (e) 24% decreased striatum mitochondrial content, likely associated to decreased NO-dependent mitochondrial biogenesis. Intermediate values were observed after 30 days of rotenone treatment. Frontal cortex tissue and mitochondria showed similar but less marked changes. Rotenone-treated rats showed mitochondrial complex I syndrome associated with cellular oxidative stress in the dopaminergic brain areas of striatum and frontal cortex, a fact that describes the high sensitivity of mitochondrial complex I to inactivation by oxidative reactions. Image 1 • Striatum and cortex mitochondria of rotenone-treated rats exhibit "complex I syndrome". • Mitochondria show decreased O 2 uptake -with NAD-dependent substrates- and NO production. • Mitochondria show increased O 2 •-, H 2 O 2 , lipid peroxidation and protein oxidation • Rotenone-treated rats show decreased striatum mitochondrial mass. • Mitochondrial complex I is highly sensitive to inactivation by oxidative reactions. [ABSTRACT FROM AUTHOR]

Methylene blue (MB) is a promising compound with a broad range of neuroprotective activity. One of therapeutic effects is the activation of mitochondrial biogenesis via Nrf2/ARE signaling cascade. Probably, mild oxidative stress caused by MB-depended H2O2 production is a trigger for activation of this signaling cascade. So mechanistically, MB can be regarded as prooxidant. We investigated the dose-dependent H2O2 production in intact brain mitochondria and showed the increase in the H2O2 production after adding as little as 50 nM MB. We have not found genotoxic effect of therapeutic concentration of MB to mitochondrial genome. 100 µM MB selectively damaged fragments of mitochondrial DNA, which correlated with the number of purine-T-G-purine (RTGR)-sequences in studied fragments. Furthermore, 20 μM MB combined with the red light caused the formation of singlet oxygen, which strongly damaged mitochondrial DNA in all studied fragments. We did not observe mitochondrial DNA lesions in brain after single intraperitoneal injection of MB in the concentration of 50 mg/kg. Furthermore, we showed the neuroprotective properties of MB pretreatments after rotenone injection. Therefore, we suggest that MB-induced mild oxidative stress does not have genotoxic effect on mitochondrial DNA. [ABSTRACT FROM AUTHOR]

Medicinal plants, as new drugs, are considered for treatment of insomnia, anxiety, depression, confusion, nausea, and vomiting symptoms. The current study aimed to evaluate the neuroprotective and antiemetic effects of Albizia. julibrissin Durazz. flower extract in the chickens. Emesis was induced by copper sulfate and ipecac (60 and 600 mg/kg, orally, respectively) and the methanolic extract (50, 100, and 200 mg/kg) were injected intraperitoneally (i.p.). Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC) content, and catalase activity as biomarkers of oxidative damage were evaluated in the brain mitochondria. All doses of extract showed significant (p < 0.001) antiemetic activity against induced emesis by copper sulfate and ipecac. Brain mitochondria function (by 50, 100, and 200 mg/kg of extract) were increased 48%, 85%, and 90% against emesis induced by ipecac and 32%, 18%, and 24% against emesis induced by copper sulfate, respectively. LPO and PC contents were significantly decreased after the administration of extract in emesis induced by copper sulfate and ipecac. A significant decrease (p < 0.01) of CAT activity was observed in the extract (200 mg/kg) group in emesis induced by copper sulfate in chickens brain mitochondria. The present study suggests that the extract had antiemetic effects against emesis induced by copper sulfate and ipecac in young chickens via peripheral and central mechanisms. Neuroprotective effect of the extract could be due to the increase in bioactive compounds, plasma antioxidants, or direct free radical scavenging that could prevent lipid and protein alteration and impede the formation of oxidative damage. [ABSTRACT FROM AUTHOR]

Methylene blue (MB) is a promising prodrug to treat mitochondrial dysfunctions that is currently being used in clinical trials for Alzheimer's disease. MB can penetrate the blood brain barrier, accumulating in brain mitochondria where it acts as a redox mediator in the electron transfer chain (ETC). Mitochondrial flavins are thought to reduce MB, which is then oxidized by cytochrome c, thereby bypassing inhibited Complex I of ETC. We found that in mouse brain mitochondria, MB fails to restore the membrane potential and respiration inhibited by antimycin. Furthermore, antimycin inhibits MB‐induced H2O2 generation. Our data suggest that the acceptor of electrons from MB is a Qo ubiquinol‐binding site of Complex III; thus, MB‐based drugs might not be helpful in mitochondrial dysfunctions involving Complex III inhibition. [ABSTRACT FROM AUTHOR]

It is widely recognized that obesity and associated metabolic changes are considered a risk factor to age-associated cognitive decline. Inflammation and increased oxidative stress in peripheral areas, following obesity, are patently the major contributory factors to the degree of the severity of brain insulin resistance as well as the progression of cognitive impairment in the obese condition. Numerous studies have demonstrated that the alterations in brain mitochondria, including both functional and morphological changes, occurred following obesity. Several studies also suggested that brain mitochondrial dysfunction may be one of underlying mechanism contributing to brain insulin resistance and cognitive impairment in the obese condition. Thus, this review aimed to comprehensively summarize and discuss the current evidence from various in vitro, in vivo, and clinical studies that are associated with obesity, brain insulin resistance, brain mitochondrial dysfunction, and cognition. Contradictory findings and the mechanistic insights about the roles of obesity, brain insulin resistance, and brain mitochondrial dysfunction on cognition are also presented and discussed. In addition, the potential therapies for obese-insulin resistance are reported as the therapeutic strategies which exert the neuroprotective effects in the obese-insulin resistant condition.

Abstract Hepatic encephalopathy (HE) is a critical clinical complication. There is a consensus that ammonia plays a pivotal role in the pathogenesis of HE. Ammonia is a neurotoxin which induces a wide range of functional disturbances in the central nervous system (CNS). On the other hand, HE is associated with the increased free radical formation, tissue inflammation, disturbed neurotransmission, astrocytes swelling, brain edema, and brain herniation. In view of the severe CNS complications ensued HE, potential therapeutic points of intervention need to be vigorously investigated. A role for CNS mitochondrial damage and energy crisis has been considered in HE. It has been found that ammonia induces mitochondrial impairment as a result of a multifaceted interaction of different signaling molecules. Hence, ammonia-induced mitochondrial injury and compromised brain energy metabolism might play a vital role in the pathogenesis of ammonia neurotoxicity. This review focuses on the concept that mitochondrial dysfunction and cellular energy crisis indeed plays a critical role in the pathogenesis of hyperammonemia-induced brain injury. Further, it will highlight the potential therapeutic value of mitochondrial protecting agents and energy providers in the management of HE. The data collected in this review might provide clues to new therapeutic interventions aimed at minimizing HE-associated complications. Graphical abstract A schematic representation for the relationship between hyperammonemia, mitochondrial impairment, and brain energy crisis. Protecting brain mitochondria might serve as a viable therapeutic point of interference in the management of hepatic encephalopathy (HE). Ca2+: Calcium; Mn2+: Manganese; NH 4 +: ammonium ion. Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5 -null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT 7 R) with the agonist molecule LP-211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain molecular alterations in Cdkl5- null male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects observed in Cdkl5- null mice and, at a molecular level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5- null mouse brains that can be restored by pharmacological stimulation of brain 5-HT 7 R. Highlights • Characterization of behavioural phenotype in fully symptomatic Cdkl5 -null mice. • The 5HT7R agonist LP-211 normalizes prepulse inhibition defects in Cdkl5 -null mice. • LP-211 treatment rescues brain mitochondrial dysfunction in Cdkl5 -null mice. • The abnormal phosphorylation of rpS6 in Cdkl5 -null cortex is restored by LP-211. [ABSTRACT FROM AUTHOR]

Abstract Glycolysis plays a key role in brain energy metabolism. The initial and rate-limiting step of brain glycolysis is catalyzed mainly by hexokinase I (HKI), the majority of which is bound to the mitochondrial outer membrane (MOM), mostly through the mitochondrial inter-membrane contact sites formed by the voltage-dependent anion channel (VDAC, outer membrane) and the adenine nucleotide translocator (ANT, inner membrane). Earlier, we proposed a mechanism for the generation of the mitochondrial outer membrane potential (OMP) as a result of partial application of the inner membrane potential (IMP) to MOM through the electrogenic ANT-VDAC-HK inter-membrane contact sites. According to this previous mechanism, the Gibbs free energy of the hexokinase reaction might modulate the generated OMP (Lemeshko, Biophys. J., 2002). In the present work, a new computational model was developed to perform thermodynamic estimations of the proposed mechanism of IMP-HKI-mediated generation of OMP. The calculated OMP was high enough to electrically regulate MOM permeability for negatively charged metabolites through free, unbound VDACs in MOM. On the other hand, the positive-inside polarity of OMP generated by the IMP-HKI-mediated mechanism is expected to protect mitochondria against elevated concentrations of cytosolic Ca2+. This computational analysis suggests that metabolically-dependent generation of OMP in the brain mitochondria, controlled by many factors that modulate VDAC1-HKI interaction, VDAC's voltage-gating properties and permeability, might represent one of the physiological mechanisms of regulation of the brain energy metabolism and of neuronal death resistance, and might also be involved in various neurodegenerative disorders, such as Alzheimer's disease. Graphical abstract Unlabelled Image Highlights • Generation of the outer membrane potential in brain mitochondria • Computational thermodynamic analysis of the proposed mechanism • Fast electrical coordination of mitochondrial oxidative phosphorylation and glycolysis • The positive outer membrane potential in Ca2+-resistance of brain mitochondria • Possible involvement of the outer membrane potential in neurodegenerative disorders [ABSTRACT FROM AUTHOR]

Among mitochondrial NADP‐reducing enzymes, nicotinamide nucleotide transhydrogenase (NNT) establishes an elevated matrix NADPH/NADP+ by catalyzing the reduction of NADP+ at the expense of NADH oxidation coupled to inward proton translocation across the inner mitochondrial membrane. Here, we characterize NNT activity and mitochondrial redox balance in the brain using a congenic mouse model carrying the mutated Nnt gene from the C57BL/6J strain. The absence of NNT activity resulted in lower total NADPH sources activity in the brain mitochondria of young mice, an effect that was partially compensated in aged mice. Nonsynaptic mitochondria showed higher NNT activity than synaptic mitochondria. In the absence of NNT, an increased release of H2O2 from mitochondria was observed when the metabolism of respiratory substrates occurred with restricted flux through relevant mitochondrial NADPH sources or when respiratory complex I was inhibited. In accordance, mitochondria from Nnt‐/‐ brains were unable to sustain NADP in its reduced state when energized in the absence of carbon substrates, an effect aggravated after H2O2 bolus metabolism. These data indicate that the lack of NNT in brain mitochondria impairs peroxide detoxification, but peroxide detoxification can be partially counterbalanced by concurrent NADPH sources depending on substrate availability. Notably, only brain mitochondria from Nnt−/− mice chronically fed a high‐fat diet exhibited lower activity of the redox‐sensitive aconitase, suggesting that brain mitochondrial redox balance requires NNT under the metabolic stress of a high‐fat diet. Overall, the role of NNT in the brain mitochondria redox balance especially comes into play under mitochondrial respiratory defects or high‐fat diet. NADPH oxidation drives H2O2 removal in biological systems. Nicotinamide nucleotide transhydrogenase (NNT) is one of the sources of NADPH regeneration in mitochondria and its relative importance seems to be organ‐specific. Overall, we demonstrated that brain mitochondria devoid of NNT possessed an impaired ability to re‐reduce NADP+ and remove H2O2, which delineated enhanced H2O2 release when substrates availability limited the participation of concurrent sources of NADPH. NNT‐null mice metabolically challenged by a fatty diet displayed lower activity of the redox‐sensitive aconitase in brain mitochondria, thus, suggesting NNT plays a role in maintaining redox balance under this condition. [ABSTRACT FROM AUTHOR]

Ca2+ influx into mitochondria is mediated by the mitochondrial calcium uniporter (MCU), whose identity was recently revealed as a 40-kDa protein that along with other proteins forms the mitochondrial Ca2+ uptake machinery. The MCU is a Ca2+-conducting channel spanning the inner mitochondrial membrane. Here, deletion of the MCU completely inhibited Ca2+ uptake in liver, heart, and skeletal muscle mitochondria. However, in brain nonsynaptic and synaptic mitochondria from neuronal somata/glial cells and nerve terminals, respectively, the MCU deletion slowed, but did not completely block, Ca2+ uptake. Under resting conditions, brain MCU-KO mitochondria remained polarized, and in brain MCU-KO mitochondria, the electrophoretic Ca2+ ionophore ETH129 significantly accelerated Ca2+ uptake. The residual Ca2+ uptake in brain MCU-KO mitochondria was insensitive to inhibitors of mitochondrial Na+/Ca2+ exchanger and ryanodine receptor (CGP37157 and dantrolene, respectively), but was blocked by the MCU inhibitor Ru360. Respiration of WT and MCU-KO brain mitochondria was similar except that for mitochondria that oxidized pyruvate and malate, Ca2+ more strongly inhibited respiration in WT than in MCU-KOmitochondria. Of note, the MCU deletion significantly attenuated but did not completely prevent induction of the permeability transition pore (PTP) in brain mitochondria. Expression level of cyclophilin D and ATP content in mitochondria, two factors that modulate PTP induction, were unaffected by MCU-KO, whereas ADP was lower in MCU-KO than in WT brain mitochondria. Our results suggest the presence of an MCU-independent Ca2+ uptake pathway in brain mitochondria that mediates residual Ca2+ influx and induction of PTP in a fraction of the mitochondrial population. [ABSTRACT FROM AUTHOR]

Here, we studied the effect of the mitochondria-targeted antioxidant SkQ1 (plastoquinone cationic derivative) on the CASP3 gene expression and caspase-3 activity in rat cerebral cortex and brain mitochondria under normal conditions and in oxidative stress induced by hyperbaric oxygenation (HBO). Under physiological conditions, SkQ1 administration (50 nmol/kg, 5 days) did not affect the CASP3 gene expression and caspase-3-like activity in the cortical cells, as well as caspase-3-like activity in brain mitochondria, but caused a moderate decrease in the content of primary products of lipid peroxidation (LPO) and an increase in the reduced glutathione (GSH) level. HBO-induced oxidative stress (0.5 MPa, 90 min) was accompanied by significant upregulation of CASP3 mRNA and caspase-3-like activity in the cerebral cortex, activation of the mitochondrial enzyme with simultaneous decrease in the GSH content, increase in the glutathione reductase activity, and stimulation of LPO. Administration of SkQ1 before the HBO session maintained the basal levels of the CASP3 gene expression and enzyme activity in the cerebral cortex cells and led to the normalization of caspase-3-like activity and redox parameters in brain mitochondria. We hypothesize that SkQ1 protects brain cells from the HBO-induced oxidative stress due to its antioxidant activity and stimulation of antiapoptotic mechanisms. [ABSTRACT FROM AUTHOR]

Wilson disease (WD) is characterized by a disrupted copper homeostasis resulting in dramatically increased copper levels, mainly in liver and brain. While copper damage to mitochondria is an established feature in WD livers, much less is known about such detrimental copper effects in other organs. We therefore assessed the mitochondrial sensitivity to copper in a tissue specific manner, namely of isolated rat liver, kidney, heart, and brain mitochondria. Brain mitochondria presented with exceptional copper sensitivity, as evidenced by a comparatively early membrane potential loss, profound structural changes already at low copper dose, and a dose-dependent reduced capacity to produce ATP. This sensitivity was likely due to a copper-dependent attack on free protein thiols and due to a decreased copper reactive defense system, as further evidenced in neuroblastoma SHSY5Y cells. In contrast, an increased production of reactive oxygen species was found to be a late-stage event, only occurring in destroyed mitochondria. We therefore propose mitochondrial protein thiols as major targets of mitochondrial copper toxicity. [ABSTRACT FROM AUTHOR]

It is widely recognized that obesity and associated metabolic changes are considered a risk factor to age-associated cognitive decline. Inflammation and increased oxidative stress in peripheral areas, following obesity, are patently the major contributory factors to the degree of the severity of brain insulin resistance as well as the progression of cognitive impairment in the obese condition. Numerous studies have demonstrated that the alterations in brain mitochondria, including both functional and morphological changes, occurred following obesity. Several studies also suggested that brain mitochondrial dysfunction may be one of underlying mechanism contributing to brain insulin resistance and cognitive impairment in the obese condition. Thus, this review aimed to comprehensively summarize and discuss the current evidence from various in vitro, in vivo , and clinical studies that are associated with obesity, brain insulin resistance, brain mitochondrial dysfunction, and cognition. Contradictory findings and the mechanistic insights about the roles of obesity, brain insulin resistance, and brain mitochondrial dysfunction on cognition are also presented and discussed. In addition, the potential therapies for obese-insulin resistance are reported as the therapeutic strategies which exert the neuroprotective effects in the obese-insulin resistant condition. [ABSTRACT FROM AUTHOR]

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is linked to cell apoptosis and abundantly expressed in brain tissue. Mitochondrial oxidative stress plays a key role in activating apoptotic pathway following cerebral ischemia reperfusion (IR) injury. Reduced glutathione (GSH) is exclusively synthesized in cytosol but distributed in mitochondria. In the present study, we investigated whether CFTR affected mitochondrial oxidative stress via regulating GSH and thereby protected neurons against apoptosis following cerebral IR. Brains were subjected to global IR by four-vessel occlusion and CFTR activator forskolin (FSK) was used in vivo. CFTR silence was performed in vitro for neurons by RNA interference. We found that FSK suppressed neuronal apoptosis whereas CFTR silence enhanced neuronal apoptosis. FSK prevented the elevations in reactive oxygen species (ROS) and caspase activities while FSK inhibited the reductions in complex I activity and mitochondrial GSH level following IR. FSK decreased mitochondrial oxidative stress partially and preserved mitochondrial function. On the contrary, CFTR silence exaggerated mitochondrial dysfunction. CFTR loss increased hydrogen peroxide (H2O2) level and decreased GSH level in mitochondria. Importantly, we showed that CFTR was located on mitochondrial membrane. GSH transport assay suggested that GSH decrease may be a consequence not a reason for mitochondrial oxidative stress mediated by CFTR disruption. Our results highlight the central role of CFTR in the pathogenesis of cerebral IR injury. CFTR regulates neuronal apoptosis following cerebral IR via mitochondrial oxidative stress-dependent pathway. The mechanism of CFTR-mediated mitochondrial oxidative stress needs further studies.Key messages: CFTR activation protects brain tissue against IR-induced apoptosis and oxidative stress.CFTR disruption enhances H2O2-induced neuronal apoptosis and CFTR loss leads to mitochondrial oxidative stress.CFTR regulates IR-induced neuronal apoptosis via mitochondrial oxidative stress.CFTR may be a potential therapeutic target to cerebral IR damage. [ABSTRACT FROM AUTHOR]

The evaluation of mitochondrial function provides the basis for the study of brain bioenergetics. However, analysis of brain mitochondrial respiration has been hindered by the low yield associated with mitochondria isolation procedures. Furthermore, isolating mitochondria or cells results in loss of the inherent complexity of the central nervous system. High-resolution respirometry (HRR), is a valuable tool to study mitochondrial function and has been used in diverse biological preparations ranging from isolated mitochondria to tissue homogenates and permeabilized tissue biopsies. Here we describe a novel methodology for evaluation of mitochondrial respiration using tissue preparations from the central nervous system, namely acute hippocampal slices from rodents, with HRR. By using acute intact hippocampal slices, tissue cytoarchitecture, intercellular communication and connectivity are preserved. Mitochondrial respiration was evaluated by using an adapted substrate-uncoupler-inhibitor titration (SUIT) protocol and the expected responses were observed. This methodology can be used to detect differences in mitochondrial function at the oxidative phosphorylation level and for studies with different brain oxidative substrates in physiological and neuropathological settings, by using a system that better represents the in vivo conditions than isolated mitochondria and/or cells. [ABSTRACT FROM AUTHOR]

The present study targeted the brain mitochondria dysfunction in Swiss albino mice through carbon tetrachloride intoxication and its treatment with Zingerone. It is proposed that brain mitochondria is the main organelle responsible for oxidative stress by producing reactive oxygen species (ROS). Swiss albino mice were divided into four groups; Group-1 was control; Group-2 was carbon tetrachloride (CCl4) toxic (1.5mg kg-1 bm i.p two days in a week.); Group-3 was pretreated with Zingerone (100 mg kg-1 b.m) a day before the administration of CCl44 and Group-4 was only Zingerone (100 mg kg-1 bm) given orally for 15days once in a day. At the end of the experiment mice were sacrificed and mitochondria were isolated from brain. Isolated brain mitochondria were further analyzed for oxidative stress marker. Thiobarbituric acid reactive substance (TBARS) content was increased significantly by CCl44 administration in Group-II as compared to the control Group-I, while the antioxidant (GSH) and other antioxidant enzyme GPx , GR, and CAT was depleted significantly in CCl4 treated Group-II as compare to control Group-I. Zingerone protected the toxicity of brain mitochondria by reducing the lipid peroxidation and enhancing the antioxidant enzyme in Group-III and there was no significant changes were noticed in Group-IV as compared to Group-I. Overall results showed the potential effects of Zingerone in protecting the neuronal cell loss by oxidative stress. Thus, the present study indicated that the Zingerone may be used as the potential therapeutic tools for the prevention of CCl4 induced brain mitochondrial toxicity. [ABSTRACT FROM AUTHOR]

Recent evidence highlights a role for sex and hormonal status in regulating cellular responses to ischemic brain injury and neurodegeneration. A key pathological event in ischemic brain injury is the opening of a mitochondrial permeability transition pore (MPT) induced by excitotoxic calcium levels, which can trigger irreversible damage to mitochondria accompanied by the release of pro-apoptotic factors. However, sex differences in brain MPT modulation have not yet been explored. Here, we show that mitochondria isolated from female mouse forebrain have a lower calcium threshold for MPT than male mitochondria, and that this sex difference depends on the MPT regulator cyclophilin D (CypD). We also demonstrate that an estrogen receptor beta (ERβ) antagonist inhibits MPT and knockout of ERβ decreases the sensitivity of mitochondria to the CypD inhibitor, cyclosporine A. These results suggest a functional relationship between ERβ and CypD in modulating brain MPT. Moreover, co-immunoprecipitation studies identify several ERβ binding partners in mitochondria. Among these, we investigate the mitochondrial ATPase as a putative site of MPT regulation by ERβ. We find that previously described interaction between the oligomycin sensitivity-conferring subunit of ATPase (OSCP) and CypD is decreased by ERβ knockout, suggesting that ERβ modulates MPT by regulating CypD interaction with OSCP. Functionally, in primary neurons and hippocampal slice cultures, modulation of ERβ has protective effects against glutamate toxicity and oxygen glucose deprivation, respectively. Taken together, these results reveal a novel pathway of brain MPT regulation by ERβ that could contribute to sex differences in ischemic brain injury and neurodegeneration. [ABSTRACT FROM AUTHOR]

Methyl jasmonate (MeJA), common in the plant kingdom, is capable of reducing articular and hepatic inflammation and oxidative stress in adjuvant-induced arthritic rats. This study investigated the actions of orally administered MeJA (75−300 mg/kg) on inflammation, oxidative stress and selected enzyme activities in the brain of Holtzman rats with adjuvant-induced arthritis. MeJA prevented the arthritis-induced increased levels of nitrites, nitrates, lipid peroxides, protein carbonyls and reactive oxygen species (ROS). It also prevented the enhanced activities of myeloperoxidase and xanthine oxidase. Conversely, the diminished catalase and superoxide dismutase activities and glutathione (GSH) levels caused by arthritis were totally or partially prevented. Furthermore, MeJA increased the activity of the mitochondrial isocitrate dehydrogenase, which helps to supply NADPH for the mitochondrial glutathione cycle, possibly contributing to the partial recovery of the GSH/oxidized glutathione (GSSG) ratio. These positive actions on the antioxidant defenses may counterbalance the effects of MeJA as enhancer of ROS production in the mitochondrial respiratory chain. A negative effect of MeJA is the detachment of hexokinase from the mitochondria, which can potentially impair glucose phosphorylation and metabolism. In overall terms, however, it can be concluded that MeJA attenuates to a considerable extent the negative effects caused by arthritis in terms of inflammation and oxidative stress.

Mitochondrial function has been closely associated with normal aging and age-related diseases. Age-associated declines in mitochondrial function, such as changes in oxygen consumption rate, cytochrome c oxidase activity of complex IV, and mitochondrial coenzyme Q (CoQ) levels, begin as early as 12 to 15 months of age in male mouse brains. Brain mitochondrial dysfunction is accompanied by increased accumulation of phosphorylated α-synuclein in the motor cortex and impairment of motor activities, which are similar characteristics of Parkinson’s disease. However, these age-associated defects are completely rescued by the administration of exogenous CoQ10 to middle-aged mice via its water solubilization by emulsification in drinking water. Further efforts to develop strategies to enhance the biological availability of CoQ10 to successfully ameliorate age-related brain mitochondrial dysfunction or neurodegenerative disorders may provide a promising anti-aging agent.

Neuronal function demands high-level energy production, and as such, a decline in mitochondrial respiration characterizes brain injury and disease. A growing number of studies, however, link brain mitochondrial function to behavioral modulation in non-diseased contexts. In the honey bee, we show for the first time that an acute social interaction, which invokes an aggressive response, may also cause a rapid decline in brain mitochondrial bioenergetics. The degree and speed of this decline has only been previously observed in the context of brain injury. Furthermore, in the honey bee, age-related increases in aggressive tendency are associated with increased baseline brain mitochondrial respiration, as well as increased plasticity in response to metabolic fuel type in vitro. Similarly, diet restriction and ketone body feeding, which commonly enhance mammalian brain mitochondrial function in vivo, cause increased aggression. Thus, even in normal behavioral contexts, brain mitochondria show a surprising degree of variation in function over both rapid and prolonged timescales, with age predicting both baseline function and plasticity in function. These results suggest that mitochondrial function is integral to modulating aggression-related neuronal signaling. We hypothesize that variation in function reflects mitochondrial calcium buffering activity, and that shifts in mitochondrial function signal to the neuronal soma to regulate gene expression and neural energetic state. Modulating brain energetic state is emerging as a critical component of the regulation of behavior in non-diseased contexts. [ABSTRACT FROM AUTHOR]

Mitochondrial respiration and ATP production are compromised by hypoxia. Naked mole rats (NMRs) are among the most hypoxiatolerant mammals and reduce metabolic rate in hypoxic environments; however, little is known regarding mitochondrial function during in vivo hypoxia exposure in this species. To address this knowledge gap, we asked whether the function of NMR brain mitochondria exhibits metabolic plasticity during acute hypoxia. Respirometry was utilized to assess whole-animal oxygen consumption rates and high-resolution respirometry was utilized to assess electron transport system (ETS) function in saponinpermeabilized NMR brain. We found that NMR whole-animal oxygen consumption rate reversibly decreased by ~85% in acute hypoxia (4 h at 3% O2). Similarly, relative to untreated controls, permeabilized brain respiratory flux through the ETS was decreased by ~90% in acutely hypoxic animals. Relative to carbonyl cyanide p-trifluoro-methoxyphenylhydrazone-uncoupled total ETS flux, this functional decrease was observed equally across all components of the ETS except for complex IV (cytochrome c oxidase), at which flux was further reduced, supporting a regulatory role for this enzyme during acute hypoxia. The maximum enzymatic capacities of ETS complexes I-V were not altered by acute hypoxia; however, the mitochondrial H+ gradient decreased in step with the decrease in ETS respiration. Taken together, our results indicate that NMR brain ETS flux and H+ leak are reduced in a balanced and regulated fashion during acute hypoxia. Changes in NMR mitochondrial metabolic plasticity mirror whole-animal metabolic responses to hypoxia. [ABSTRACT FROM AUTHOR]

The beneficial effects of Fibroblast Growth Factor 21 (FGF21) on metabolic function and neuroprotection have been shown in earlier research. We have previously shown that the Dipeptidyl Peptidase 4 inhibitor, vildagliptin, also led to improved insulin sensitivity and brain function in the obese-insulin resistant condition. However, the comparative efficacy on the improvement of metabolic function and neuroprotection between FGF21 and vildagliptin in the obese-insulin resistant condition has never been investigated. Twenty-four male Wistar rats were divided into two groups, and received either a normal diet (ND, n = 6) or a high fat diet (HFD, n = 18) for 16 weeks. At week 13, the HFD-fed rats were divided into three subgroups (n = 6/subgroup) to receive either a vehicle, recombinant human FGF21 (0.1 mg/kg/day) or vildagliptin (3 mg/kg/day), for four weeks. ND-fed rats were given a vehicle for four weeks. The metabolic parameters and brain function were subsequently investigated. The results demonstrated that the rats fed on HFD had obese-insulin resistance, increased systemic inflammation, brain mitochondrial dysfunction, increased brain apoptosis, impaired hippocampal plasticity, and demonstrated cognitive decline. FGF21 and vildagliptin effectively attenuated peripheral insulin resistance, brain mitochondrial dysfunction, brain apoptosis and cognitive decline. However, only FGF21 treatment led to significantly reduced body weight gain, visceral fat, systemic inflammation, improved hippocampal synaptic plasticity, enhanced FGF21 mediated signaling in the brain leading to prevention of early cognitive decline. These findings suggest that FGF21 exerts greater efficacy than vildagliptin in restoring metabolic function as well as brain function in cases of obese-insulin resistant rats. [ABSTRACT FROM AUTHOR]

Phosphorylation of some membrane-bound proteins in the mitochondria of rat liver and brain is regulated by Ca2+ and cAMP acting as secondary messengers. These proteins are the main myelin components: 46 kDa 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP) and two isoforms of the myelin basic protein (MBP) with molecular weights of 17 and 21.5 kDa, which we have identified previously and found outside myelin in rat brain mitochondria. The phosphorylation level of CNP and both MBP isoforms increases when the mitochondrial permeability transition pore (mPTP) is opened. It is known that protein kinases A and C in heart mitochondria are directly bound to mPTP regulator proteins and are able to modulate the pore function. It is shown in this study that the inhibitors of protein kinases A (H-89) and C (staurosporin, Go 6976, and GF 109203 X) decrease the phosphorylation level of CNP and two MBP isoforms allowing us to assume that they are the targets of the signaling protein kinases A and C. [ABSTRACT FROM AUTHOR]

The mitochondria have a fundamental role in both cellular energy supply and oxidative stress regulation and are target of the effects of sex steroids, particularly the neuroprotective ones. Aging is associated with a decline in the levels of different steroid hormones, and this decrease may underline some neural dysfunctions. Besides, modifications in mitochondrial functions associated with aging processes are also well documented. In this review, we will discuss studies that describe the modifications of brain mitochondrial function and of steroid levels associated with physiological aging and with neurodegenerative diseases. A special emphasis will be placed on describing and discussing our recent findings concerning the concomitant study of mitochondrial function (oxidative phosphorylation, oxidative stress) and brain steroid levels in both young (3-month-old) and aged (20-month-old) male and female mice. [ABSTRACT FROM AUTHOR]

CB1 receptors are functionally present within brain mitochondria (mtCB1), although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. [ABSTRACT FROM AUTHOR]

The oxygen consumption rate (OCR) in brain mitochondria is significantly lower in aged mice than in young mice, and the reduced OCR is rescued by administration of water-solubilized CoQ 10 to aged mice via drinking water. However, the mechanism behind this remains unclear. Here, we show that the activity of respiratory complex IV (CIV) in brain mitochondria declined in aged mice than in young mice, with no significant change in individual respiratory complex levels and their supercomplex assembly. Reduced CIV activity in the aged mice coincided with reduced binding of optic atrophy 1 (OPA1) to CIV. Both reduced activity and OPA1 binding of CIV were rescued by water-solubilized CoQ 10 administration to aged mice via drinking water. OCR and the activity and OPA1 binding of CIV in isolated brain mitochondria from aged mice were restored by incubation with CoQ 10 , but not in the presence of 15-deoxy-prostaglandin J 2 , an inhibitor of a GTPase effector domain-containing GTPase such as OPA1 and DRP1. By contrast, the CoQ 10 -responsive restoration of OCR in the isolated mitochondria was not inhibited by Mdivi-1, a selective inhibitor of DRP1. Thus, we propose a novel function of OPA1 in regulating the CIV activity in brain mitochondria in response to CoQ 10 . [ABSTRACT FROM AUTHOR]

The pesticides are used in several fields of agriculture and farms to protect crops against harmful insects and herbs. The increased and uncontrolled use of these pollutants is very hazardous for the population health. Consumption of contaminated food matrices with these pesticides could impair the cell integrity and its molecular function. The main aim of this present study was to evaluate the alteration of the integrity of mitochondrial membranes and respiratory chain potential in the brain of rats exposed during 90 days to acetamiprid (AC), organochlorine of the new generation. After oral administration of AC in rats with 3.14 mg/kg of body weight, the results of this current study showed enhance in mitochondrial oxidative stress status by significant decrease of glutathione (GSH) level, glutathione pyroxidase (GPx), and catalase (CAT) activities. On the other hand, there is an increase in the enzymatic activity of the glutathione s-transferase (GST) and superoxide dismutase (SOD); at the same time, the MDA level was also highly increased. Furthermore, evaluation results of brain mitochondrial integrity revealed a significant increase in membrane permeability and mitochondrial swelling in rats exposed chronically to AC. Instead, other results of this present work showed a significant decrease in mitochondrial respiration potent (O consumption) in acetamiprid-treated rats. In conclusion, the long duration exposition of the animals to AC has led to respiratory chain dysfunction, disturbance of matrix oxidative status, and a loss of mitochondrial membranes integrity. [ABSTRACT FROM AUTHOR]

Alcohol hangover (AH) is the pathophysiological state after a binge-like drinking. We have previously demonstrated that AH induced bioenergetics impairments in a total fresh mitochondrial fraction in brain cortex and cerebellum. The aim of this work was to determine free radical production and antioxidant systems in non-synaptic mitochondria and synaptosomes in control and hangover animals. Superoxide production was not modified in non-synaptic mitochondria while a 17.5% increase was observed in synaptosomes. A similar response was observed for cardiolipin content as no changes were evidenced in non-synaptic mitochondria while a 55% decrease in cardiolipin content was found in synaptosomes. Hydrogen peroxide production was 3-fold increased in non-synaptic mitochondria and 4-fold increased in synaptosomes. In the presence of deprenyl, synaptosomal H 2 O 2 production was 67% decreased in the AH condition. Hydrogen peroxide generation was not affected by deprenyl addition in non-synaptic mitochondria from AH mice. MAO activity was 57% increased in non-synaptic mitochondria and 3-fold increased in synaptosomes. Catalase activity was 40% and 50% decreased in non-synaptic mitochondria and synaptosomes, respectively. Superoxide dismutase was 60% decreased in non-synaptic mitochondria and 80% increased in synaptosomal fractions. On the other hand, GSH (glutathione) content was 43% and 17% decreased in synaptosomes and cytosol. GSH-related enzymes were mostly affected in synaptosomes fractions by AH condition. Acetylcholinesterase activity in synaptosomes was 11% increased due to AH. The present work reveals that AH provokes an imbalance in the cellular redox homeostasis mainly affecting mitochondria present in synaptic terminals. [ABSTRACT FROM AUTHOR]

The rate of oxygen consumption by glutamate- and malate-energized rat brain mitochondria, which was stimulated by an uncoupler 2,4-dinitrophenol (DNP), declined in the presence of a prooxidant tert-butyl hydroperoxide. Preincubation with gangliosides GM1 or GD1a at micromolar (but not nanomolar) concentrations significantly slowed down this decline in the mitochondrial respiration, as shown by measuring absolute respiratory rates and ratios of the mitochondrial respiratory rate in the presence of DNP to the basal respiratory rate ( V / V ). Gangliosides GM1 and GD1a also slowed down a decline in the DNP-stimulated mitochondrial respiration induced by long-term incubation ('aging') of mitochondria on ice. The data obtained are likely to reflect a prooxidant-induced reduction in the activity of enzymes of the mitochondrial respiratory chain as well as a GM1- and GD1a-induced decrease in the degree of their inactivation. Interestingly, in the presence of the Trk receptor tyrosine kinase inhibitor (K252a) this effect of gangliosides was not manifested in any way. Our data suggest that the direct impact of gangliosides on mitochondrial signaling pathways, specifically on the Trk receptor tyrosine kinase, plays a certain role in the mechanism of their protective effect on cerebral neurons and, probably, neuroglia. [ABSTRACT FROM AUTHOR]

Exercise is known to have numerous beneficial effects. Recent studies indicate that exercise improves mitochondrial energetics not only in skeletal muscle but also in other tissues. While exercise elicits positive effects on memory, neurogenesis, and synaptic plasticity, the effects of exercise on brain mitochondrial energetics remain relatively unknown. Herein, we studied the effects of exercise training in old and young mice on brain mitochondrial energetics, in comparison to known effects on peripheral tissues that utilize fatty acid oxidation. Exercise improved the capacity for muscle and liver to oxidize palmitate in old mice, but not young mice. In the brain, exercise increased rates of respiration and reactive oxygen species (ROS) production in the old group only while utilizing complex I substrates, effects that were not seen in the young group. Coupled complex I to III enzymatic activity was significantly increased in old trained versus untrained mice with no effect on coupled II to III enzymatic activity. Mitochondrial protein content and markers of mitochondrial biogenesis (PGC-1α and TFAM) were not affected by exercise training in the brain, in contrast to the skeletal muscle of old mice. Brain levels of the autophagy marker LC3-II and protein levels of other signaling proteins that regulate metabolism or transport (BDNF, HSP60, phosphorylated mTOR, FNDC5, SIRT3) were not significantly altered. Old exercised mice showed a significant increase in DRP1 protein levels in the brain without changes in phosphorylation, while MFN2 and OPA1 protein levels were unchanged. Our results suggest that exercise training in old mice can improve brain mitochondrial function through effects on electron transport chain function and mitochondrial dynamics without increasing mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]