Krebs cycle dysfunction shapes epigenetic landscape of chromatin: Novel insights into mitochondrial regulation of aging process

Although there is a substantial literature that mitochondria have a crucial role in the aging process, the mechanism has remained elusive. The role of reactive oxygen species, mitochondrial DNA injuries, and a decline in mitochondrial quality control has been proposed. Emerging studies have demonstrated that Krebs cycle intermediates, 2-oxoglutarate (also known as α-ketoglutarate), succinate and fumarate, can regulate the level of DNA and histone methylation. Moreover, citrate, also a Krebs cycle metabolite, can enhance histone acetylation. Genome-wide screening studies have revealed that the aging process is linked to significant epigenetic changes in the chromatin landscape, e.g. global demethylation of DNA and histones and increase in histone acetylation. Interestingly, recent studies have revealed that the demethylases of DNA (TET1-3) and histone lysines (KDM2-7) are members of 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzymes are activated by oxygen, iron and the major Krebs cycle intermediate, 2-oxoglutarate, whereas they are inhibited by succinate and fumarate. Considering the endosymbiont origin of mitochondria, it is not surprising that Krebs cycle metabolites can control the gene expression of host cell by modifying the epigenetic landscape of chromatin. It seems that age-related disturbances in mitochondrial metabolism can induce epigenetic reprogramming, which promotes the appearance of senescent phenotype and degenerative diseases.     

Storage diseases: new insights into sphingolipid functions

Studying human diseases can help us to uncover important processes in normal cells. Cell biologists have recently focused on inherited sphingolipid-storage diseases. Eukaryotic life is characterized by internal membranes of various compositions, and sphingolipids are a small but important part of these membranes. Compositional differences between cellular membranes are maintained by sorting and sphingolipids are thought to organize this process by forming ordered domains of increased thickness in the bilayer. Here, we describe the impact of sphingolipid accumulation on the sorting of endocytic membranes and discuss the proposed basis for the pathology of these diseases at the cellular level.     

Dyskeratosis congenita: molecular insights into telomerase function, ageing and cancer

Dyskeratosis congenita (DC) is a severe, inherited, bone marrow failure syndrome, with associated cutaneous and noncutaneous abnormalities. DC patients also show signs of premature ageing and have an increased occurrence of cancer. DC can originate through: (1) mutations in DKC1, which result in X-linked recessive DC; (2) mutations in the RNA component of telomerase (TERC), which result in autosomal dominant DC (AD-DC); and (3) mutations in other, currently uncharacterized, genes, which result in autosomal recessive DC (AR-DC). As DKC1 encodes dyskerin, a protein component of small nucleolar ribonucleoprotein (snoRNP) particles, which are important in ribosomal RNA processing, DC was initially described as a disorder of defective ribosomal biogenesis. Subsequently, dyskerin and TERC were shown to closely associate with each other in the telomerase complex, and DC has since come to be regarded as a telomerase deficiency disorder characterised by shorter telomeres. These findings demonstrate the importance of telomerase in humans and highlight how its deficiency (through DKC1 and TERC mutations) results in multiple abnormalities including premature ageing, bone marrow failure and cancer. Identification of the gene(s) involved in AR-DC will help to define the pathophysiology of DC further, as well as expand our insights into telomere function, ageing and cancer.     

Structural and functional insights into CST tethering in Tetrahymena thermophila telomerase

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Infectogenomics: insights from the host genome into infectious diseases

Five years into the human postgenomic era, we are gaining considerable knowledge about host-pathogen interactions through host genomes. This "infectogenomics" approach should yield further insights into both diagnostic and therapeutic advances, as well as normal cellular function.     

Human tears reveal insights into corneal neovascularization

Corneal neovascularization results from the encroachment of blood vessels from the surrounding conjunctiva onto the normally avascular cornea. The aim of this study is to identify factors in human tears that are involved in development and/or maintenance of corneal neovascularization in humans. This could allow development of diagnostic tools for monitoring corneal neovascularization and combination monoclonal antibody therapies for its treatment. In an observational case-control study we enrolled a total of 12 patients with corneal neovascularization and 10 healthy volunteers. Basal tears along with reflex tears from the inferior fornix, superior fornix and using a corneal bath were collected along with blood serum samples. From all patients, ocular surface photographs were taken. Concentrations of the pro-angiogenic cytokines interleukin (IL)-6, IL-8, Vascular Endothelial Growth Factor (VEGF), Monocyte Chemoattractant Protein 1 (MCP-1) and Fas Ligand (FasL) were determined in blood and tear samples using a flow cytometric multiplex assay. Our results show that the concentration of pro-angiogenic cytokines in human tears are significantly higher compared to their concentrations in serum, with highest levels found in basal tears. Interestingly, we could detect a significantly higher concentration of IL- 6, IL-8 and VEGF in localized corneal tears of patients with neovascularized corneas when compared to the control group. This is the first study of its kind demonstrating a significant difference of defined factors in tears from patients with neovascularized corneas as compared to healthy controls. These results provide the basis for future research using animal models to further substantiate the role of these cytokines in the establishment and maintenance of corneal neovascularization.     

Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting

Alterations in muscle mitochondrial bioenergetics during cancer cachexia were previously suggested; however, the underlying mechanisms are not known. So, the goal of this study was to evaluate mitochondrial phospholipid remodeling in cancer-related muscle wasting and its repercussions to respiratory chain activity and fiber susceptibility to apoptosis.     

Chronic transplant dysfunction and transplant arteriosclerosis: new insights into underlying mechanisms

Although effective in the short-term, clinical solid-organ transplantation has not achieved its goals as a long-term treatment for patients with end-stage organ failure. Development of so-called chronic transplant dysfunction (CTD)is now recognised as the predominant cause of allograft loss long-term (after the first post-operative year) following transplantation. CTD has the remarkable histological feature that the luminal areas of intragraft arteries become obliterated, predominantly with vascular smooth muscle cells intermingled with some inflammatory cells. The development of this transplant vasculopathy,referred to as transplant arteriosclerosis (TA), is a multifactorial process and many risk factors have been identified. However, the precise pathogenetic mechanisms leading to TA are largely unknown and, as a result, current prevention and treatment protocols are inadequate. This review discusses the risk factors for TA and current views on the pathogenetic mechanisms leading to this vasculopathy. We argue here that host-derived cells contribute to the development of these vascular lesions, and propose that TA results from a normal vascular repair process that proceeds beyond the needs of functional repair. Guided by the proposed sequence of events, we finally discuss possible directions for future intervention strategies to prevent TA after solid-organ transplantation.     

Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics

The precise causal factors for obsessive-compulsive disorder (OCD) are not known, although, decades of research have honed in on the cortico-striatal-thalamo-cortical (CSTC) circuitry in the brain as a critical pathway involved in obsessions and the intimately linked compulsive-repetitive behaviors. Recent progress in human and mouse genetics have led to the identification of novel candidate susceptibility genes, which in turn have facilitated a more focused approach to unraveling the nature of circuitry dysfunction in OCD. The ability to perform invasive techniques in genetic animal models of OCD will be crucial for rapid advances in this field, and as such we review the most recent developments and highlight the importance of searching out common circuitry defects underlying compulsive-repetitive behaviors.     

Human aneuploidy: mechanisms and new insights into an age-old problem

Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.     

Oxysterol-Binding Protein: new insights into lipid transport functions and human diseases

Oxysterol-binding protein (OSBP) mediates lipid exchange between organelles at membrane contact sites, thereby regulating lipid dynamics and homeostasis. How OSBP's lipid transfer function impacts health and disease remain to be elucidated. In this review, we first summarize the structural characteristics and lipid transport functions of OSBP, and then focus on recent progresses linking OSBP with fatty liver disease, diabetes, lysosome-related diseases, cancer and viral infections, with the aim of discovering novel therapeutic strategies for common human diseases.     

Seeing the light: new insights into the molecular pathogenesis of retinal diseases

In the past, most treatments for retinal diseases have been empirical. Steroids and/or laser photocoagulation and/or surgery have been tried for almost every condition with little or no understanding of the underlying disease. Over the past several years vision researchers have uncovered molecular components of processes, such as visual transduction and the visual cycle, that are critical for visual function, and identified other molecules that lead to dysfunction and disease processes such as neovascularization and macular edema. It is becoming clear that dysregulation of certain molecules can have major effects on retinal structure and function. Studies in animal models have suggested that inhibiting or augmenting levels of a single molecule can have major effects in complex disease processes. Although several molecules probably contribute to neovascularization and excessive vascular permeability in the eye, blockade of vascular endothelial growth factor (VEGF) has remarkable beneficial effects in animal models that have now been proven to apply to human diseases in clinical trials. Intraocular injection of VEGF antagonists has revolutionized the treatment of choroidal neovascularization (CNV) and macular edema and serves as a model of targeted ocular pharmacotherapy. Significant progress elucidating the molecular pathogenesis of several disease processes in the eye may soon lead to new treatments following the lead of VEGF antagonists. Initial treatments that provide benefit from frequent intraocular injections are likely to be followed by sustained delivery of drugs and/or prolonged protein delivery by gene transfer. The eye has entered the era of molecular therapy.     

Anatomic insights into the thigmonastic style tissue in Marantaceae

The irreversible style movement in Marantaceae is one of the quickest plant movements ever recorded. It is largely based on a special tissue construction, which is analysed herein for the first time. Histological sections, fluorescence and different electron microscopic techniques are used to study the style tissue of eight species in six genera of the Marantaceae. Tissue sections prior to the thigmonastic movement are only obtained after ether or chloroform narcosis. The tissue in the bending zone of the style has the construction of a lamellar collenchyma with elongated cells and extended intercellular spaces. The thicker cell walls abut the intercellular spaces, while the thinner walls between adjacent cells are extraordinarily porous. The tissue is thus characterised by strongly perforated cell bundles which are able to slide alongside each other and the intercellular spaces. Cell-wall loosening starts about 24 h before flowering and is interpreted as a result of enzymatic ageing processes. It is also found in other members of the Zingiberales, but only the Marantaceae take advantage of the maceration process. We conclude that the specific tissue construction contributes to the rapid style movement. It combines qualities for stabilisation (collenchyma), pliability (intercellular spaces) and water transport (extremely porous tissue), thus supporting the irreversible style bending by a sudden and final shift of fluid.