Modification Of Energy Metabolism Research Articles

New variants expand the neurological phenotype of COQ7 deficiency.

The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy.

Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.

Metabolomics of 3D cell co-culture reveals alterations in energy metabolism at the cross-talk of colorectal cancer-adipocytes.

Colorectal cancer (CRC) is the third most incident and the second most lethal malignant tumor. Despite the recognized association between obesity and CRC, further clarification is necessary regarding the lipids that are overexpressed during the development of CRC. In this scenario, the combination of metabolomics and a three-dimensional (3D) co-culture model involving CRC tumor cells and lipids can enhance the knowledge of energy metabolism modifications at the cross-talk between colorectal cancer and adipocytes. This study aimed to screen potential metabolites in the three dimensional (3D) co-culture of CRC and adipocytes by investigating the metabolome composition of this co-culture released into the extracellular space, which is known as the secretome. Pre-adipocyte cells (3T3-L1), human colon carcinoma (HT-29), and the 3D co-culture (3T3-L1 + HT-29) were cultured for the secretome obtention. Then, ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was employed to analyze the metabolomics of each secretome. Overall, 3.731 molecules were detected independent of the cell culture. When comparing the three cultures, 105 molecules presented a statistically significant difference in abundance between groups. Among these molecules, 16 were identified, with a particular emphasis on six lipids (PG 20:0, octadecenal, 3-Hydroxytetracosanoyl-CoA, 9,10-dihydroxy-octadecenoic acid, palmitoleic acid, and PA 18:4) and one amino acid derivative (acetylglutamic acid), which presented significant scores during the partial least-squares discriminant analysis (PLS-DA). Although it is too early to determine the possible impact of such molecules in a CRC microenvironment, these results open new avenues for further studies on the energy metabolism at the cross-talk of colorectal cancer adipocytes.

The potential role of glucose metabolism, lipid metabolism, and amino acid metabolism in the treatment of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease, which can cause progressive deterioration of motor function causing muscle stiffness, tremor, and bradykinesia. In this review, we hope to describe approaches that can improve the life of PD patients through modifications of energy metabolism. The main pathological features of PD are the progressive loss of nigrostriatal dopaminergic neurons and the production of Lewy bodies. Abnormal aggregation of α-synuclein (α-Syn) leading to the formation of Lewy bodies is closely associated with neuronal dysfunction and degeneration. The main causes of PD are said to be mitochondrial damage, oxidative stress, inflammation, and abnormal protein aggregation. Presence of abnormal energy metabolism is another cause of PD. Many studies have found significant differences between neurodegenerative diseases and metabolic decompensation, which has become a biological hallmark of neurodegenerative diseases. In this review, we highlight the relationship between abnormal energy metabolism (Glucose metabolism, lipid metabolism, and amino acid metabolism) and PD. Improvement of key molecules in glucose metabolism, fat metabolism, and amino acid metabolism (e.g., glucose-6-phosphate dehydrogenase, triglycerides, and levodopa) might be potentially beneficial in PD. Some of these metabolic indicators may serve well during the diagnosis of PD. In addition, modulation of these metabolic pathways may be a potential target for the treatment and prevention of PD.

Aromatic amino acids play a harmonizing role in prostate cancer: A metabolomics-based cross-sectional study.

BackgroundProstate cancer (PCa) is a common health problem worldwide. The rate of this disease is likely to grow by 2021. PCa is a heterogeneous disorder, and various biochemical factors contribute to the development of this disease. The metabolome is the complete set of metabolites in a cell or biological sample and represents the downstream end product of the omics. Hence, to model PCa by computational systems biology, a preliminary metabolomics-based study was used to compare the metabolome profile pattern between healthy and PCa men.ObjectiveThis study was carried out to highlight energy metabolism modification and assist the prognosis and treatment of disease with unique biomarkers.Materials and MethodsIn this cross-sectional research, 26 men diagnosed with stage-III PCa and 26 healthy men with normal PSA levels were enrolled. Urine was analyzed with proton nuclear magnetic resonance (H-NMR) spectroscopy, accompanied by the MetaboAnalyst web-based platform tool for metabolomics data analysis. Partial least squares regression discriminant analysis was applied to clarify the separation between the two groups. Outliers were documented and metabolites determined, followed by identifying biochemical pathways.ResultsOur findings reveal that modifications in aromatic amino acid metabolism and some of their metabolites have a high potential for use as urinary PCa biomarkers. Tryptophan metabolism (p 0.001), tyrosine metabolism (p 0.001), phenylalanine, tyrosine and tryptophan biosynthesis (p 0.001), phenylalanine metabolism (p = 0.01), ubiquinone and other terpenoid-quinone biosynthesis (p = 0.19), nitrogen metabolism (p = 0.21), and thiamine metabolism (p = 0.41) with Q (0.198) and R (0.583) were significantly altered.ConclusionThe discriminated metabolites and their pathways play an essential role in PCa causes and harmony.

Systemic and local cardiac inflammation after experimental long bone fracture, traumatic brain injury and combined trauma in mice

BackgroundTrauma is the leading cause of death and disability worldwide, especially in the young population. Cardiac injuries are an independent predictor for a poor overall outcome after trauma. The aim of the present study was to analyze systemic inflammation as well as local cardiac inflammation after experimental limb-, neuro- and combined trauma in mice.MethodsMale C57BL/6 mice received either a closed tibia fracture (Fx), isolated traumatic brain injury (TBI) or a combination of both (Fx ​+ ​TBI). Control animals underwent sham procedure. After 6 and 24 ​h, systemic levels of inflammatory mediators were analyzed, respectively. Locally, cardiac inflammation and cardiac structural alterations were investigated in left ventricular tissue of mice 6 and 24 ​h after trauma.ResultsMice showed enhanced systemic inflammation after combined trauma, which was manifested by increased levels of KC, MCP-1 and G-CSF. Locally, mice exhibited increased expression of inflammatory cytokines (IL-1β, TNF) in heart tissue, which was probably mediated via toll-like receptor (TLR) signaling. Furthermore, mice demonstrated a redistribution of connexin 43 in cardiac tissue, which appeared predominantly after combined trauma. Besides inflammation and structural cardiac alterations, expression of glucose transporter 4 (GLUT4) mRNA was increased in the heart early after TBI and after combination of TBI and limb fracture, indicating a modification of energy metabolism. Early after combination of TBI and tibia fracture, nitrosative stress was increased, manifested by elevation of nitrotyrosine in cardiac tissue. Finally, mice showed a trend of increased systemic levels of cardiac troponin I and heart-fatty acid binding protein (HFABP) after combined trauma, which was associated with a significant decrease of troponin I and HFABP mRNA expression in cardiac tissue after TBI and combination of TBI and limb fracture.ConclusionMice exhibited early cardiac alterations as well as alterations in cardiac glucose transporter expression, indicating a modification of energy metabolism, which might be linked to increased systemic- and local cardiac inflammation after limb-, neuro- and combined trauma. These cardiac alterations might predispose individuals for secondary cardiac damage after trauma that might compromise cardiac function after TBI and long bone fracture.Translational potential statementInjuries to the head and extremities frequently occur after severe trauma. In our study, we analyzed the effects of closed tibia fracture, isolated TBI, and the combination of both injuries with regard to the development of post-traumatic secondary cardiac injuries.

Mechanism of Biological Aging-A Review

Aging is a universal, inherent, natural phenomenon that occurs in all organism. Aging involves morphologicaland functional changes in cellular and extracellular components leading to progressive decline in mostbiological functions. It causes reduction in strength, basal metabolism, sexual activity and the body’sdefenses.Aging is the progressive decline in the maintenance of homeostasis, which leads to decreased response ofthe body against internal and external stress. It involves imbalance between free radicals and the antioxidantmechanism lead to damaged cells, tissues, and organs resulting in age related changes.With age there is modifications in energy metabolism, insulin sensitivity, neuroendocrine function andinduction of hormesis response. Telomere shortening, mitochondrial dysfunction, increase of oxidativestress, alteration of insulin-like growth factor and growth hormone signaling are considered to be importantcontributors of aging process.Recently many genes and changes in gene expression have been found associated with aging which affectsmany biological processes and are associated with senescence and oxidative stress.This review focuses on the underlying mechanism of biological aging. With an increase in the number ofelderly population and the patients of age-related diseases, it is becoming increasingly important to considerthese in the field of research. We have attempted to discuss the different aging mechanism along with thenewer concepts, which can give a direction for the future research studies.

Real-Time PCR Analysis of Metabolism-Related Genes in a Long-Lived Model of C. elegans.

In the nematode Caenorhabditis elegans, the mammalian tumor suppressor p53 ortholog CEP-1(C. elegans p53-like protein) is associated not only with the stress response, germline apoptosis, and meiotic chromosome segregation but also with longevity through the modification of energy metabolism during aging. The mitochondrial respiration-related gene sco-1 in C. elegans is orthologous to the human SCO1 gene and a target of p53/CEP-1. Using quantitative real-time polymerase chain reaction (PCR) analysis, we recently found that the expression levels of sco-1 gene were increased in wild-type C. elegans in an aging-related manner and decreased in long-lived cep-1 mutants. Here, we describe the relative quantitative strategy using a commercial real-time PCR system to detect more accurately differences in the levels of expressed genes between long-lived and wild-type C. elegans strains. To estimate the expression levels of target genes compared with wild-type using relative quantification, we used the expression levels of an endogenous control gene, such as a housekeeping gene. In addition, it is critical to normalize differences in the expression levels of the common housekeeping gene among the strains analyzed for an accurate comparison of the quantitative expression levels of target genes.

Effect of high hydrostatic pressure on mitochondrial activity, reactive oxygen species level and developmental competence of cultured pig embryos

High hydrostatic pressure (HHP) has been previously used to increase mammalian oocyte and embryo tolerance on subsequent stresses related with different assisted reproductive technologies. Nevertheless, the mechanisms for HHP-induced stress responses in early embryos have not been yet well understood. Previous studies focused mainly on HHP-modified gene expression while possible changes in cellular functions, including modification of energy metabolism and oxidative stress were neglected. Therefore, we aimed to analyze the effect of HHP treatment on the efficiency of subsequent in vitro pig embryos culture in NCSU-23 medium, on mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) level during their pre-implantation development. Porcine embryos were exposed to the hydrostatic pressure of 20 MPa and their quick response to such stress was analyzed 1 h later. In comparison with control embryos, we detected lower ΔΨm by ∼13% only in expanded blastocysts as well as decreased ROS level by ∼30% and ∼42% at the morula and expanded blastocyst stages, respectively. After HHP-treatment at transcriptionally inactive zygote stage and subsequent embryo culture, long-time responses were found: (1) at expanded blastocyst stage manifesting by ΔΨm decrease by ∼16%, (2) at the morula and expanded blastocyst stages in the form of ROS level reduction by ∼38% and ∼33% respectively. Following HHP stress applied at the transcriptionally active morula stage the long-time response in the expanded blastocysts as a decrease of ΔΨm by ∼19% and ROS level by ∼37% was observed. The percentage of obtained expanded blastocysts was higher after culture of HHP-treated zygotes in comparison to the control. Moreover, expanded blastocysts developed in vitro from both HHP-treated zygotes or morulae, exhibited higher total number of cells per blastocyst, higher number of cells in the inner cell mass as well as lower number of TUNEL-positive nuclei per blastocyst and lower TUNEL index, when compared to untreated embryos. Therefore, the HHP stress applied at the zygote stage, enhances developmental potential and quality of in vitro obtained porcine blastocysts due to the both decreased ΔΨm and ROS level. Our findings may contribute to better understanding of the mechanism of HHP-mediated modifications of energy metabolism and oxidative stress during in vitro development of pig embryos.

A Multi-Bioassay Integrated Approach to Assess the Antifouling Potential of the Cyanobacterial Metabolites Portoamides.

The cyclic peptides portoamides produced by the cyanobacterium Phormidium sp. LEGE 05292 were previously isolated and their ability to condition microcommunities by allelopathic effect was described. These interesting bioactive properties are, however, still underexplored as their biotechnological applications may be vast. This study aims to investigate the antifouling potential of portoamides, given that a challenge in the search for new environmentally friendly antifouling products is to find non-toxic natural alternatives with the ability to prevent colonization of different biofouling species, from bacteria to macroinvertebrates. A multi-bioassay approach was applied to assess portoamides antifouling properties, marine ecotoxicity and molecular mode of action. Results showed high effectiveness in the prevention of mussel larvae settlement (EC50 = 3.16 µM), and also bioactivity towards growth and biofilm disruption of marine biofouling bacterial strains, while not showing toxicity towards both target and non-target species. Antifouling molecular targets in mussel larvae include energy metabolism modifications (failure in proton-transporting ATPases activity), structural alterations of the gills and protein and gene regulatory mechanisms. Overall, portoamides reveal a broad-spectrum bioactivity towards diverse biofouling species, including a non-toxic and reversible effect towards mussel larvae, showing potential to be incorporated as an active ingredient in antifouling coatings.

The modification of mitochondrial energy metabolism and histone of goat somatic cells under small molecules compounds induction.

In recent years, induced pluripotent stem cells (iPSCs) technique is able to allow us to generate pluripotency from somatic cells in vitro through the over expression of several transcription factors. Normally, viral vectors and transcription factors are commonly used on iPSC technique, which could cause many barriers on further application. In this study, we attempt to process a new method to obtain pluripotency from goat somatic cells in vitro under fully chemically defined condition. The results showed that chemically induced pluripotent stem cells-like cells (CiPSC-like cells) colonies were generated from goat ear fibroblasts by fully small-molecule compounds. Those three dimensions colonies were similar with mouse iPSCs in morphology and had strong positive alkaline phosphatase (AP) activity and expressed pluripotency related genes OCT4, SOX2, NANOG, CDH1, TDGF, GDF3, DAX1, REX1, which determined by RT-PCR. Those colonies could also differentiate into different cell types derived from three germ layers proved by RT-PCR and immunofluorescence assays. The expression of glycolysis-related genes about PGAM1, KPYM2 and HXK2 in CiPSC-like colonies formation groups was significantly higher than their parental fibroblasts, but not in the non-CiPSC-like colonies formation group. The expression of histone acetylation and methylation-related genes, HAT1 and SMYD3, was not significantly up-regulated within different groups compared to their parental fibroblasts, respectively. Yet, the expression of histone methylation-related gene, KDM5B, was significantly up-regulated on the cells from non-colonies formation group compared to parental fibroblasts, but the expression of KDM5B of the cells from CiPSC-like cell colonies was not significantly difference compared to that of parental fibroblasts. In conclusion, this is the first report that CiPSC-like cells could be generated in vitro from goat rather than just mouse under fully chemically defined condition. The generation of CiPSC-like colonies may be depended on the correct modification of energy metabolism and histone epigenetic during the reprogramming, rather than just the over-expression of those pluripotency-related genes. This study will strongly support us to further establish the stable goat CiPSC lines without any integration of exogenous genes.

Modification of Energy Metabolism and Higher Brain Function by Feeding Rhythm

A molecular clock exists within almost all organizations in a living body, and these clocks influence the periodicity of many physiological phenomena such as eating behaviors, the sleep-wake cycle, and hormone secretion. Especially, a living body's energy metabolism is involved with the molecular clocks genetically driven in peripheral tissues, which act in strong relation to eating rhythms. However, the possibility that rhythms may also have an inverse influence has recently been pointed out. In this manuscript, we review the outline of circadian rhythms, then refer to the possibility that a clock gene in the peripheral tissues, capable of being changed by eating rhythms, may influence sleep-wake regulation and energy metabolism.

Non-targeted metabolomics reveals alterations in liver and plasma of gilt-head bream exposed to oxybenzone

The extensive use of the organic UV filter oxybenzone has led to its ubiquitous occurrence in the aquatic environment, causing an ecotoxicological risk to biota. Although some studies reported adverse effects, such as reproductive toxicity, further research needs to be done in order to assess its molecular effects and mechanism of action. Therefore, in the present work, we investigated metabolic perturbations in juvenile gilt-head bream (Sparus aurata) exposed over 14 days via the water to oxybenzone (50 mg/L). The non-targeted analysis of brain, liver and plasma extracts was performed by means of UHPLC-qOrbitrap MS in positive and negative modes with both C18 and HILIC separation. Although there was no mortality or alterations in general physiological parameters during the experiment, and the metabolic profile of brain was not affected, the results of this study showed that oxybenzone could perturb both liver and plasma metabolome. The pathway enrichment suggested that different pathways in lipid metabolism (fatty acid elongation, α-linolenic acid metabolism, biosynthesis of unsaturated fatty acids and fatty acid metabolism) were significantly altered, as well as metabolites involved in phenylalanine and tyrosine metabolism. Overall, these changes are signs of possible oxidative stress and energy metabolism modification. Therefore, this research indicates that oxybenzone has adverse effects beyond the commonly studied hormonal activity, and demonstrates the sensitivity of metabolomics to assess molecular-level effects of emerging contaminants.

Comparative Proteomic and Transcriptomic Analysis of Follistatin-Induced Skeletal Muscle Hypertrophy.

Skeletal muscle, the most abundant body tissue, plays vital roles in locomotion and metabolism. Myostatin is a negative regulator of skeletal muscle mass. In addition to increasing muscle mass, Myostatin inhibition impacts muscle contractility and energy metabolism. To decipher the mechanisms of action of the Myostatin inhibitors, we used proteomic and transcriptomic approaches to investigate the changes induced in skeletal muscles of transgenic mice overexpressing Follistatin, a physiological Myostatin inhibitor. Our proteomic workflow included a fractionation step to identify weakly expressed proteins and a comparison of fast versus slow muscles. Functional annotation of altered proteins supports the phenotypic changes induced by Myostatin inhibition, including modifications in energy metabolism, fiber type, insulin and calcium signaling, as well as membrane repair and regeneration. Less than 10% of the differentially expressed proteins were found to be also regulated at the mRNA level but the Biological Process annotation, and the KEGG pathways analysis of transcriptomic results shows a great concordance with the proteomic data. Thus this study describes the most extensive omics analysis of muscle overexpressing Follistatin, providing molecular-level insights to explain the observed muscle phenotypic changes.

Reduced up-regulation of the nitric oxide pathway and impaired endothelial and smooth muscle functions in the female type 2 diabetic goto-kakizaki rat heart

BackgroundType 2 diabetes is associated with greater relative risk of cardiovascular diseases in women than in men, which is not well understood. Consequently, we have investigated if male and female displayed differences in cardiac function, energy metabolism, and endothelial function which could contribute to increased cardiovascular complications in type 2 diabetic female.MethodsMale and female Control and type 2 diabetic Goto-Kakizaki (GK) isolated rat hearts were perfused during 28 min with a physiological buffer before freeze-clamping for biochemical assays. High energy phosphate compounds and intracellular pH were followed using 31P magnetic resonance spectroscopy with simultaneous measurement of contractile function. Nitric oxide (NO) pathway and endothelium-dependent and independent vasodilatations were measured as indexes of endothelial function. Results were analyzed via two-way ANOVA, p < 0.05 was considered as statistically significant.ResultsMyocardial function was impaired in male and female diabetic versus Control groups (p < 0.05) without modification of energy metabolism. Coronary flow was decreased in both diabetic versus Control groups but to a higher extent in female GK versus male GK rat hearts (p < 0.05). NO production was up-regulated in diabetic groups but to a less extent in female GK rat hearts (p < 0.05). Endothelium-dependent and independent vasodilatations were impaired in female GK rat compared with male GK (p < 0.05) and female Control (p < 0.05) rat hearts.ConclusionsWe reported here an endothelial damage characterized by a reduced up-regulation of the NO pathway and impaired endothelial and smooth muscle functions, and coronary flow rates in the female GK rat hearts while energy metabolism was normal. Whether these results are related to the higher risk of cardiovascular complications among type 2 diabetic female needs to be further elicited in the future.

Remote ischemic preconditioning with a specialized protocol activates the non-neuronal cardiac cholinergic system and increases ATP content in the heart

Ischemic preconditioning (IPC) renders the targeted organ resistant to prolonged ischemic insults, leading to organoprotection. Among several means to achieve IPC, we reported that remote ischemic preconditioning (RIPC) activates the non-neuronal cardiac cholinergic system (NNCCS) to accelerate de novo ACh synthesis in cardiomyocytes. In the current study, we aimed to optimize a specific protocol to most efficiently activate NNCCS using RIPC. In this study, we elucidated that the protocol with 3min of ischemia repeated three times increased cardiac ChAT expression (139.2±0.4%; P<0.05) as well as ACh (14.2±2.0×10−8M; P<0.05) and ATP content (2.13±0.19μmol/g tissue; P<0.05) in the heart. Moreover, in the specific protocol, several characteristic responses against energy starvation and for obtaining adequate energy were observed; therefore, it is suggested that RIPC evokes a robust response by the heart to activate NNCCS through the modification of energy metabolism.

Lateral gene transfer and gene duplication played a key role in the evolution of Mastigamoeba balamuthi hydrogenosomes.

Lateral gene transfer (LGT) is an important mechanism of evolution for protists adapting to oxygen-poor environments. Specifically, modifications of energy metabolism in anaerobic forms of mitochondria (e.g., hydrogenosomes) are likely to have been associated with gene transfer from prokaryotes. An interesting question is whether the products of transferred genes were directly targeted into the ancestral organelle or initially operated in the cytosol and subsequently acquired organelle-targeting sequences. Here, we identified key enzymes of hydrogenosomal metabolism in the free-living anaerobic amoebozoan Mastigamoeba balamuthi and analyzed their cellular localizations, enzymatic activities, and evolutionary histories. Additionally, we characterized 1) several canonical mitochondrial components including respiratory complex II and the glycine cleavage system, 2) enzymes associated with anaerobic energy metabolism, including an unusual D-lactate dehydrogenase and acetyl CoA synthase, and 3) a sulfate activation pathway. Intriguingly, components of anaerobic energy metabolism are present in at least two gene copies. For each component, one copy possesses an mitochondrial targeting sequence (MTS), whereas the other lacks an MTS, yielding parallel cytosolic and hydrogenosomal extended glycolysis pathways. Experimentally, we confirmed that the organelle targeting of several proteins is fully dependent on the MTS. Phylogenetic analysis of all extended glycolysis components suggested that these components were acquired by LGT. We propose that the transformation from an ancestral organelle to a hydrogenosome in the M. balamuthi lineage involved the lateral acquisition of genes encoding extended glycolysis enzymes that initially operated in the cytosol and that established a parallel hydrogenosomal pathway after gene duplication and MTS acquisition.

Calorie Restriction and Dietary Restriction Mimetics: A Strategy for Improving Healthy Aging and Longevity

Improvements in health care have increased human life expectancy in recent decades, and the elderly population is thus increasing in most developed countries. Unfortunately this still means increased years of poor health or disability. Since it is not yet possible to modify our genetic background, the best anti-aging strategy is currently to intervene on environmental factors, aiming to reduce the incidence of risk factors of poor health. Calorie restriction (CR) with adequate nutrition is the only non-genetic, and the most consistent non-pharmacological intervention that extends lifespan in model organisms from yeast to mammals, and protects against the deterioration of biological functions, delaying or reducing the risk of many age-related diseases. The biological mechanisms of CR's beneficial effects include modifications in energy metabolism, oxidative stress, insulin sensitivity, inflammation, autophagy, neuroendocrine function and induction of hormesis/xenohormesis response. The molecular signalling pathways mediating the anti-aging effect of CR include sirtuins, peroxisome proliferator activated receptor G coactivator-1α, AMP-activated protein kinase, insulin/insulin growth factor-1, and target of rapamycin, which form a pretty interacting network. However, most people would not comply with such a rigorous dietary program; research is thus increasingly aimed at determining the feasibility and efficacy of natural and/or pharmacological CR mimetic molecules/ treatments without lowering food intake, particularly in mid- to late-life periods. Likely candidates act on the same signalling pathways as CR, and include resveratrol and other polyphenols, rapamycin, 2-deoxy-D-glucose and other glycolytic inhibitors, insulin pathway and AMP-activated protein kinase activators, autophagy stimulators, alpha-lipoic acid, and other antioxidants.

Role of Polyphosphate in Mitochondria: From Modification of Energy Metabolism to Induction of the Cell Death

Inorganic polyphosphate (polyP) is found in all living organisms ranging from bacteria to mammals. PolyP plays multiple physiological functions, which are distinct and dependent on the type of organism and the subcellular localization of the polymer. Recently we demonstrated that polyP levels are dependent on the cell metabolism and can be changed by mitochondrial substrates and inhibitors. We propose the existence of a feedback mechanism where polyP production and cell energy metabolism regulate each other. In order to investigate this we study the effect of polyP on mitochondrial oxygen consumption. We have found that application of short polyP (14 phosphate residues) or medium polyP (70 ortophosphates) significantly increase the level of respiratory coefficient by activation of state V3 and inhibition of V4 compare to control. Importantly, both short and medium polyP significantly reduced efficiency of oxidative phosphorylation (ADP/O ratio). It has previously been reported that polyP can modify membrane permeability for ions that can be a trigger for changes in mitochondrial metabolism. Furthermore polyP has been linked to activation of the mitochondrial permeability transition pore (mPTP) in different cells that also can be activated by calcium. Long, medium, and in lower degree, short polyP increase permeability of de-energised mitochondria for Ca2+. This effect was dependent on inhibitor of mPTP - cyclosporine A. We also found that long polyP (130 orthophosphates) caused cell death in primary neurons and astrocytes, while medium (70) polyP had a much smaller effect and short (14) did not cause any. Thus, polyP has a multiple action on mitochondrial function from modification of mitochondrial energy metabolism to stimulation of calcium permeability and cell death.

XPC silencing in normal human keratinocytes triggers metabolic alterations through NOX-1 activation-mediated reactive oxygen species

Cancer cells utilize complex mechanisms to remodel their bioenergetic properties. We exploited the intrinsic genomic stability of xeroderma pigmentosum C (XPC) to understand the inter-relationships between genomic instability, reactive oxygen species (ROS) generation, and metabolic alterations during neoplastic transformation. We showed that knockdown of XPC (XPC KD) in normal human keratinocytes results in metabolism remodeling through NADPH oxidase-1 (NOX-1) activation, which in turn leads to increased ROS levels. While enforcing antioxidant defenses by overexpressing catalase, CuZnSOD, or MnSOD could not block the metabolism remodeling, impaired NOX-1 activation abrogates both alteration in ROS levels and modifications of energy metabolism. As NOX-1 activation is observed in human squamous cell carcinomas (SCCs), the blockade of NOX-1 could be a target for the prevention and the treatment of skin cancers. This article is part of a Special Issue entitled: Bioenergetics of Cancer.