Brain Mitochondria as a Therapeutic Target for Carnosic Acid.

Carnosic acid (CA), a diterpene obtained mainly from Rosmarinus officinalis and Salvia officinalis, exerts antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. At least in part, those benefits are associated with the ability that CA modulates mitochondrial physiology. CA attenuated bioenergetics collapse and redox impairments in the mitochondria obtained from brain cells exposed to several toxicants in both in vitro and in vivo experimental models. CA is a potent inducer of the major modulator of the redox biology in animal cells, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of a myriad of genes whose products are involved with cytoprotection in different contexts. Moreover, CA upregulates signaling pathways related to the degradation of damaged mitochondria (mitophagy) and with the synthesis of these organelles (mitochondrial biogenesis). Thus, CA may be considered an agent that induces mitochondrial renewal, depending on the circumstances. In this review, we discuss about the mechanisms of action by which CA promotes mitochondrial protection in brain cells.

ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD), now better known as Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD) and its progression to Nonalcoholic Steatohepatitis (NASH), more recently referred to as Metabolic (Dysfunction)-Associated Steatohepatitis (MASH) are the most common causes of liver failure and chronic liver damage. The new names emphasize the metabolic involvement both in relation to liver function and pathological features with extrahepatic manifestations. This study aims to explore the role of the immunometabolic enzyme ATP citrate lyase (ACLY), with a critical function in lipogenesis, carbohydrate metabolism, gene expression and inflammation. METHODS: ACLY function was investigated in TNFα-triggered human hepatocytes and in PBMC-derived macrophages from MASH patients. Evaluation of expression levels was carried out by western blotting and/or RT-qPCR. In the presence or absence of ACLY inhibitors, ROS, lipid peroxidation and GSSG oxidative stress biomarkers were quantified. Chromatin immunoprecipitation (ChIP), transient transfections, immunocytochemistry, histone acetylation quantitation were used to investigate ACLY function in gene expression reprogramming. IL-6 and IL-1ß were quantified by Lumit immunoassays. RESULTS: Mechanistically, ACLY inhibition reverted lipid accumulation and oxidative damage while reduced secretion of inflammatory cytokines in TNFα-triggered human hepatocytes. These effects impacted not only on lipid metabolism but also on other crucial features of liver function such as redox status and production of inflammatory mediators. Moreover, ACLY mRNA levels together with those of malic enzyme 1 (ME1) increased in human PBMC-derived macrophages from MASH patients when compared to age-matched healthy controls. Remarkably, a combination of hydroxycitrate (HCA), the natural ACLY inhibitor, with red wine powder (RWP) significantly lowered ACLY and ME1 mRNA amount as well as IL-6 and IL-1ß production in macrophages from subjects with MASH. CONCLUSION: Collectively, our findings for the first time highlight a broad spectrum of ACLY functions in liver as well as in the pathogenesis of MASH and its diagnostic and therapeutic potential value.

Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97.

Sigma-2 receptor (S2R) is a S2R ligand-binding site historically associated with reportedly 21.5 kDa proteins that have been linked to several diseases, such as cancer, Alzheimer's disease, and schizophrenia. The S2R is highly expressed in various tumors, where it correlates with the proliferative status of the malignant cells. Recently, S2R was reported to be the transmembrane protein TMEM97. Prior to that, we had been investigating the translocator protein (TSPO) as a potential 21.5 kDa S2R candidate protein with reported heme and sterol associations. Here, we investigate the contributions of TMEM97 and TSPO to S2R activity in MCF7 breast adenocarcinoma and MIA PaCa-2 (MP) pancreatic carcinoma cells. Additionally, the role of the reported S2R-interacting partner PGRMC1 was also elucidated. Proximity ligation assays and co-immunoprecipitation show a functional association between S2R and TSPO. Moreover, a close physical colocalization of TMEM97 and TSPO was found in MP cells. In MCF7 cells, co-immunoprecipitation only occurred with TMEM97 but not with PGRMC1, which was further confirmed by confocal microscopy experiments. Treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduced co-immunoprecipitation of both TMEM97 and PGRMC1 in immune pellets of immunoprecipitated TSPO in MP cells. To the best of our knowledge, this is the first suggestion of a (functional) interaction between TSPO and TMEM97 that can be affected by S2R ligands.

Association between des-acyl ghrelin at fasting and predictive index of muscle derangement, metabolic markers and eating disorders: a cross-sectional study in overweight and obese adults.

Background: This study aimed to analyse the impact of des-acyl and acyl ghrelin (AG) on a wide range of muscular and metabolic markers and in order to discover the possible relationships and interactions of des-acylated ghrelin (DAG) on eating disorders.Materials & Methods: A total of 88 subjects (64 women and 24 men, with a mean age of 43 years and a mean body mass index (BMI) of 30.20 ± 3.27 kg/m2) were enrolled in the cross-sectional study.Results: The findings showed that for each unit of increase of free fat mass index (FFMI), levels of DAG decreased by -41.11 pg/mL (p < 0.05). Moreover, similar associations with DAG were found for insulin (ß = -30.67; p < 0.001), leptin (ß = -0.64; p < 0.05), body weight (ß = -14.36; p < 0.001), and free fat mass (FFM) (ß = -30.67; p < 0.001). In addition, associations were found between DAG and resting energy expenditure (REE) (ß = -0.84; p = 0.05) and the binge eating scale (BES) in which a unit increase of the BES score Q3 (depression) correlated with a decrease of DAG levels (ß = -9.98; p = 0.08). Further, a unit increase of AG/DAG ratio correspond with an increase in body weight (ß = 12.20; p < 0.05), BMI (ß = 4.70; p < 0.05) and fat mass (ß = 7.30; p < 0.05). However, the AG/DAG ratio was not associated with FFMI (ß = 2.61; p = 0.165) and FFML/BMI (ß = -0,064; p = 0.625).Conclusion: This study suggests that higher levels of DAG at fasting are indices of poor muscle mass, insulin resistance and depression.

An update on magnesium and bone health.

In 2009 EFSA Panel concludes that a cause and effect relationship has been established between the dietary intake of magnesium (Mg) and maintenance of normal bone. After 2009, numerous studies have been published, but no reviews have made an update on this topic. So, the aim of this narrative review was to consider the state of the art since 2009 on relationship between Mg blood levels, Mg dietary intake and Mg dietary supplementation (alone or with other micronutrients; this last topic has been considered since 1990, because it is not included in the EFSA claims) and bone health in humans. This review included 28 eligible studies: nine studies concern Mg blood, 12 studies concern Mg intake and seven studies concern Mg supplementation, alone or in combination with other nutrients. From the various studies carried out on the serum concentration of Mg and its relationship with the bone, it has been shown that lower values are related to the presence of osteoporosis, and that about 30-40% of the subjects analyzed (mainly menopausal women) have hypomagnesaemia. Various dietetic investigations have shown that many people (about 20%) constantly consume lower quantities of Mg than recommended; moreover, in this category, a lower bone mineral density and a higher fracturing risk have been found. Considering the intervention studies published to date on supplementation with Mg, most have used this mineral in the form of citrate, carbonate or oxide, with a dosage varying between 250 and 1800 mg. In all studies there was a benefit both in terms of bone mineral density and fracture risk.

Bergamot phytosome improved visceral fat and plasma lipid profiles in overweight and obese class I subject with mild hypercholesterolemia: A randomized placebo controlled trial.

Bergamot has been traditionally used for the relief of diseases related to oxidative stress. Our aim was to investigate the effect of bergamot phytosome on visceral adipose tissue (VAT) and on metabolic profile, in overweight and obese subjects with mild hypercholesterolemia. A total of 64 participants were randomized into two groups for 12 weeks: a supplemented group (33 individuals, BMI 27 ± 3 kg/m2 receiving 500 mg of bergamot phytosome, two daily tablets) and placebo group (31 subjects, BMI 28 ± 3 kg/m2 , two daily tablets). As to the within differences, the parameters of VAT, total and LDL-cholesterol were significantly decreased in the bergamot phytosome group, but not in the placebo group. As to between-group differences, a statistically significant interaction between time and group, that is, the change in score over time differs between the two groups was observed 30 days after supplementation for VAT (p-value = .005), total cholesterol (p-value <.0002), and LDL (p = .004) in respect to placebo. The other parameters (glucose, insulin, Homeostasis Model Assessment, high-density lipoprotein cholesterol, triglycerides, fat free mass, fat mass) were not significant. In conclusion, this clinical study gives evidence that bergamot phytosome provides beneficial effects, such as decrease of VAT and modulation of metabolic alterations, after just 30 days of supplementation, resulting a very promising protection of cardiovascular health.

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target.

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

A Phenylacetamide Resveratrol Derivative Exerts Inhibitory Effects on Breast Cancer Cell Growth.

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.

New synthesized polyoxygenated diarylheptanoids suppress lipopolysaccharide-induced neuroinflammation.

In neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, neuroinflammation induced by the microglial activation plays a crucial role. In effort to develop effective anti-neuroinflammatory compounds, different new linear polyoxygenated diarylheptanoids were synthesized. In LPS-triggered BV-2 microglial cells their ability to reduce the concentration of IL-6 and TNF-α pro-inflammatory cytokines was evaluated. Moreover, their effect on NF-κB and ATP citrate lyase (ACLY), a recently emerged target of metabolic reprogramming in inflammation, was assessed. Finally, we turned our attention to inflammatory mediators derived from the cleavage of citrate catalyzed by ACLY: prostaglandin E2, nitric oxide and reactive oxygen species. All compounds showed null or minimal cytotoxicity; most of them had a great anti-neuroinflammatory activity. Diarylheptanoids 6b and 6c, bearing a halide atom and benzyl ether protective groups, exhibited the best effect since they blocked the secretion of all inflammatory mediators analyzed and reduced NF-κB and ACLY protein levels.

A structural equation model to assess the pathways of body adiposity and inflammation status on dysmetabolic biomarkers via red cell distribution width and mean corpuscular volume: a cross-sectional study in overweight and obese subjects.

BACKGROUND: A study has been performed in overweight and obese subjects to assess the effects of adiposity and inflammation indicators on dysmetabolic biomarkers via red cell distribution width (RDW) and mean corpuscular volume (MCV), taking into account pro-antioxidant balance. METHODS: Data from 166 overweight subjects were analyzed by a path analysis model using structural equation modelling (SEM) to evaluate the direct and indirect pathway effects of adiposity, measured by body mass index (BMI) and waist circumference (WC), and inflammation status, measured by pro-antioxidant balance [reactive oxygen species (ROS)], lag-time and slope and C-reactive protein (CRP) values on dysmetabolic biomarkers, via RDW and MCV. RESULTS: BMI was strongly linked to CRP and ROS levels. Moreover, there was a significant negative decrease of MCV (1.546 femtoliters) linked to BMI indirectly via high CRP levels. Furthermore, WC affected RDW, indicating a possible mediatory role for RDW in relation to the relationship between WC and homeostatic model assessment (HOMA), insulin and high density lipoprotein (HDL), respectively. This was evident by the elevated HOMA and insulin levels and the decreased levels of HDL. Finally, ROS-related markers did not affect directly RDW and MCV. CONCLUSION: The reported outcomes suggest that RDW might play a mediatory role in the relationship between WC and the dysmetabolic outcomes in overweight and obese individuals. CRP seems to modulate the linkage between BMI and MCV. This study provides the backbone structure for future scenarios and lays the foundation for further research on the role of RDW and MCV as suitable biomarkers for the assessment of cardiovascular disease (HDL-cholesterol), inflammatory bowels and insulin resistance.

Clinical trials on pain lowering effect of ginger: A narrative review.

Ginger has a pain-reducing effect and it can modulate pain through various mechanisms: inhibition of prostaglandins via the COX and LOX-pathways, antioxidant activity, inibition of the transcription factor nf-kB, or acting as agonist of vanilloid nociceptor. This narrative review summarizes the last 10-year of randomized controlled trials (RCTs), in which ginger was traditionally used as a pain reliever for dysmenorrhea, delayed onset muscle soreness (DOMS), osteoarthritis (AO), chronic low back pain (CLBP), and migraine. Regarding dysmenorrhea, six eligible studies suggest a promising effect of oral ginger. As concerned with DOMS, the four eligible RCTs suggested a reduction of inflammation after oral and topical ginger administration. Regarding knee AO, nine RCTs agree in stating that oral and topical use of ginger seems to be effective against pain, while other did not find significant differences. One RCT considered the use of ginger in migraine and suggested its beneficial activity. Finally, one RCT evaluated the effects of Swedish massage with aromatic ginger oil on CLBP demonstrated a reduction in pain. The use of ginger for its pain lowering effect is safe and promising, even though more studies are needed to create a consensus about the dosage of ginger useful for long-term therapy.

Polycystic ovary syndrome management: a review of the possible amazing role of berberine.

PURPOSE: The therapy of polycystic ovary syndrome (PCOS) is based on synthetic hormones associated with lifestyle changes, but these therapies cannot be taken continuously, especially by women who would like to become pregnant. Thus, nutraceutical compounds were investigated as possible agents for treatment of PCOS. Berberine is shown to be effective against insulin resistance and obesity, particularly against visceral adipose tissue (VAT). Because of these properties, researchers theorized that berberine could be effective in PCOS treatment. METHODS: The aim of this narrative review was to assess the state of the art about the use of berberine in PCOS management. RESULTS: This review included 5 eligible studies. Despite the number of studies considered being low, the number of women studied is high (1078) and the results are interesting. Two authors find out that berberine induced a redistribution of adipose tissue, reducing VAT in the absence of weight loss and improved insulin sensitivity, quite like metformin. One author demonstrated that berberine improved the lipid pattern. Moreover, three authors demonstrated that berberine improved insulin resistance in theca cells with an improvement of the ovulation rate per cycle, so berberine is also effective on fertility and live birth rates. CONCLUSIONS: Finally, berberine is safe to use in premenopausal women who want to get pregnant and showed few side effects in all the cited studies. In conclusion, the use of berberine for PCOS is safe and promising, even if more studies are needed to create a consensus about the dosage of berberine useful for long-term therapy.

The Role of Glutamine in the Complex Interaction between Gut Microbiota and Health: A Narrative Review.

The scientific literature has demonstrated that glutamine is one of the main beneficial amino acids. It plays an important role in gut microbiota and immunity. This paper provides a critical overview of experimental studies (in vitro, in vivo, and clinical) investigating the efficacy of glutamine and its effect on gut microbiota. As a result of this review, we have summarized that glutamine could affect gut microbiota via different mechanisms including the reduction in the ratio of Firmicutes to Bacteroidetes, with the activation of NF-κB and PI3K-Akt pathways, reducing the intestinal colonization (Eimeria lesions) and bacterial overgrowth or bacterial translocation, increasing the production of secretory immunoglobulin A (SIgA) and immunoglobulin A+ (IgA+) cells in the intestinal lumen, and decreasing asparagine levels. The potential applications of glutamine on gut microbiota include, but are not limited to, the management of obesity, bacterial translocation and community, cytokines profiles, and the management of side effects during post-chemotherapy and constipation periods. Further studies and reviews are needed regarding the effects of glutamine supplementation on other conditions in humans.

Transcriptional Regulation Factors of the Human Mitochondrial Aspartate/Glutamate Carrier Gene, Isoform 2 (SLC25A13): USF1 as Basal Factor and FOXA2 as Activator in Liver Cells.

Mitochondrial carriers catalyse the translocation of numerous metabolites across the inner mitochondrial membrane, playing a key role in different cell functions. For this reason, mitochondrial carrier gene expression needs tight regulation. The human SLC25A13 gene, encoding for the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), catalyses the electrogenic exchange of aspartate for glutamate plus a proton, thus taking part in many metabolic processes including the malate-aspartate shuttle. By the luciferase (LUC) activity of promoter deletion constructs we identified the putative promoter region, comprising the proximal promoter (-442 bp/-19 bp), as well as an enhancer region (-968 bp/-768 bp). Furthermore, with different approaches, such as in silico promoter analysis, gene silencing and chromatin immunoprecipitation, we identified two transcription factors responsible for SLC25A13 transcriptional regulation: FOXA2 and USF1. USF1 acts as a positive transcription factor which binds to the basal promoter thus ensuring SLC25A13 gene expression in a wide range of tissues. The role of FOXA2 is different, working as an activator in hepatic cells. As a tumour suppressor, FOXA2 could be responsible for SLC25A13 high expression levels in liver and its downregulation in hepatocellular carcinoma (HCC).

Micronutrients Dietary Supplementation Advices for Celiac Patients on Long-Term Gluten-Free Diet with Good Compliance: A Review.

Background and objective: Often micronutrient deficiencies cannot be detected when patient is already following a long-term gluten-free diet with good compliance (LTGFDWGC). The aim of this narrative review is to evaluate the most recent literature that considers blood micronutrient deficiencies in LTGFDWGC subjects, in order to prepare dietary supplementation advice (DSA). Materials and methods: A research strategy was planned on PubMed by defining the following keywords: celiac disease, vitamin B12, iron, folic acid, and vitamin D. Results: This review included 73 studies. The few studies on micronutrient circulating levels in long-term gluten-free diet (LTGFD) patients over 2 years with good compliance demonstrated that deficiency was detected in up to: 30% of subjects for vitamin B12 (DSA: 1000 mcg/day until level is normal, then 500 mcg), 40% for iron (325 mg/day), 20% for folic acid (1 mg/day for 3 months, followed by 400-800 mcg/day), 25% for vitamin D (1000 UI/day or more-based serum level or 50,000 UI/week if level is <20 ng/mL), 40% for zinc (25-40 mg/day), 3.6% of children for calcium (1000-1500 mg/day), 20% for magnesium (200-300 mg/day); no data is available in adults for magnesium. Conclusions: If integration with diet is not enough, starting with supplements may be the correct way, after evaluating the initial blood level to determine the right dosage of supplementation.

New Insights into Behçet's Syndrome Metabolic Reprogramming: Citrate Pathway Dysregulation.

To date, a major research effort on Behçet's syndrome (BS) has been concentrated on immunological aspects. Little is known about the metabolic reprogramming in BS. Citrate is an intermediary metabolite synthesized in mitochondria, and when transported into the cytosol by the mitochondrial citrate carrier-SLC25A1-encoded protein-it is cleaved into acetyl-CoA and oxaloacetate by ATP citrate lyase (ACLY). In induced macrophages, mitochondrial citrate is necessary for the production of inflammatory mediators. The aim of our study was to evaluate SLC25A1 and ACLY expression levels in BS patients. Following a power analysis undertaken on few random samples, the number of enrolled patients was set. Thirty-nine consecutive BS patients fulfilling ISG criteria, and 21 healthy controls suitable for age and sex were recruited. BS patients were divided into two groups according to the presence (active) or absence (inactive) of clinical manifestations. Real-time PCR experiments were performed on PBMCs to quantify SLC25A1 and ACLY mRNA levels. Data processing through the Kruskal-Wallis test and Dunn's multiple comparison test as post hoc showed higher SLC25A1 and ACLY mRNA levels in BS patients compared to those in healthy controls. Therefore, SLC25A1 and ACLY upregulation suggests that metabolic reprogramming in BS involves the citrate pathway dysregulation.

Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines.

Significant metabolic changes occur in the shift from resting to activated cellular status in inflammation. Thus, changes in expression of a large number of genes and extensive metabolic reprogramming gives rise to acquisition of new functions (e.g. production of cytokines, intermediates for biosynthesis, lipid mediators, PGE, ROS and NO). In this context, mitochondrial carriers, which catalyse the transport of solute across mitochondrial membrane, change their expression to transport mitochondrially produced molecules, among which citrate and succinate, to be used as intracellular signalling molecules in inflammation. This review summarises the mitochondrial carriers studied so far that are, directly or indirectly, involved in inflammation.

Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation.

The mitochondrial citrate-malate exchanger (CIC), a known target of acetylation, is up-regulated in activated immune cells and plays a key role in the production of inflammatory mediators. However, the role of acetylation in CIC activity is elusive. We show that CIC is acetylated in activated primary human macrophages and U937 cells and the level of acetylation is higher in glucose-deprived compared to normal glucose medium. Acetylation enhances CIC transport activity, leading to a higher citrate efflux from mitochondria in exchange with malate. Cytosolic citrate levels do not increase upon activation of cells grown in deprived compared to normal glucose media, indicating that citrate, transported from mitochondria at higher rates from acetylated CIC, is consumed at higher rates. Malate levels in the cytosol are lower in activated cells grown in glucose-deprived compared to normal glucose medium, indicating that this TCA intermediate is rapidly recycled back into the cytosol where it is used by the malic enzyme. Additionally, in activated cells CIC inhibition increases the NADP+/NADPH ratio in glucose-deprived cells; this ratio is unchanged in glucose-rich grown cells due to the activity of the pentose phosphate pathway. Consistently, the NADPH-producing isocitrate dehydrogenase level is higher in activated glucose-deprived as compared to glucose rich cells. These results demonstrate that, in the absence of glucose, activated macrophages increase CIC acetylation to enhance citrate efflux from mitochondria not only to produce inflammatory mediators but also to meet the NADPH demand through the actions of isocitrate dehydrogenase and malic enzyme.

The contribution of the citrate pathway to oxidative stress in Down syndrome.

Inflammatory conditions and oxidative stress have a crucial role in Down syndrome (DS). Emerging studies have also reported an altered lipid profile in the early stages of DS. Our previous works demonstrate that citrate pathway activation is required for oxygen radical production during inflammation. Here, we find up-regulation of the citrate pathway and down-regulation of carnitine/acylcarnitine carrier and carnitine palmitoyl-transferase 1 genes in cells from children with DS. Interestingly, when the citrate pathway is inhibited, we observe a reduction in oxygen radicals as well as in lipid peroxidation levels. Our preliminary findings provide evidence for a citrate pathway dysregulation, which could be related to some phenotypic traits of people with DS.

The mitochondrial side of epigenetics.

The bidirectional cross talk between nuclear and mitochondrial DNA is essential for cellular homeostasis and proper functioning. Mitochondria depend on nuclear contribution for much of their functionality, but their activities have been recently recognized to control nuclear gene expression as well as cell function in many different ways. Epigenetic mechanisms, which tune gene expression in response to environmental stimuli, are key regulatory events at the interplay between mitochondrial and nuclear interactions. Emerging findings indicate that epigenetic factors can be targets or instruments of mitochondrial-nuclear cross talk. Additionally, the growing interest into mtDNA epigenetic modifications opens new avenues into the interaction mechanisms between mitochondria and nucleus. In this review we summarize the points of mitochondrial and nuclear reciprocal control involving epigenetic factors, focusing on the role of mitochondrial genome and metabolism in shaping epigenetic modulation of gene expression. The relevance of the new findings on the methylation of mtDNA is also highlighted as a new frontier in the complex scenario of mitochondrial-nuclear communication.