16,968 research outputs found
Mitochondrial metabolism and energy sensing in tumor progression
No full textEnergy homeostasis is pivotal for cell fate since metabolic regulation, cell proliferation and death are strongly dependent on the balance between catabolic and anabolic pathways. In particular, metabolic and energetic changes have been observed in cancer cells even before the discovery of oncogenes and tumor suppressors, but has been neglected for a long time. Instead, during the past 20 years a renaissance of the study of tumor metabolism has led to a revised and more accurate sight of the metabolic landscape of cancer cells. In this scenario, genetic, biochemical and clinical evidences place mitochondria as key actors in cancer metabolic restructuring, not only because there are energy and biosynthetic intermediates manufacturers, but also because occurrence of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA has been associated to different types of cancer. Here we provide an overview of the possible mechanisms modulating mitochondrial energy production and homeostasis in the intriguing scenario of neoplastic cells, focusing on the double-edged role of 5′-AMP activated protein kinase in cancer metabolism
The Suffering Animal. On the Weakness and the Power of the Living
No full textThe following PhD dissertation aims to provide a philosophical investigation of the contemporary debate on the human-animal relationship. Starting from a reassessment of modern debate on Descartes’ animal-machine paradigm – polemically built upon a critique of the “official philosophical narration” of current animal studies -, I will then track down the theoretical coordinates of what I named the paradigm of the suffering animal. The suffering animal is a materialist thesis on the condition of the living, which, while atheistically contesting the metaphysical structure of western axiology, it eventually redefines and re-establishes ethics on the experience of suffering. The suffering animal claims the fragility and the vulnerability of the living matter we are all, as living beings, made of. By comparing Darwin’s theory of evolution by natural selection and Nietzsche’s notion of will power, I will highlight how contemporary anti-metaphysical understanding of the human-animal relationship developed through two main guidelines. Indeed, beside the suffering animal, there stands the powerful animal, an alternative materialist paradigm claiming rather the power of life and the living beings’ right to express and perform their inner vitality against all those subtle restrictions set by western traditional morality. The analysis contained in the following book examines the commonalities and the disagreements between these two paradigms. Such a confrontation will be carried out through the philosophical productions of two very different Twentieth-Century thinker: Primo Levi and Gilles Deleuze. The ultimate aim of this dissertation is to define the “ethical equilibrium” between aspects of the living, such as weakness and power, joy and suffering, which tends to exclude one another. What is at stake in such an equilibrium is the possibility for our civilization to ground effectively the chance of equality inside and out the border of our species. This might be possible if the suffering animal and the powerful animal harbouring in each of us succeed in standing one to one without rising up one another
The Background of Mitochondrial DNA Haplogroup J Increases the Sensitivity of Leber's Hereditary Optic Neuropathy Cells to 2,5-Hexanedione Toxicity
No full textLeber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD) on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts) carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad implications for other neurodegenerative disorders such as Parkinson's disease
Mitochondrial Respiratory Supercomplexes in Physiology and Diseases
No full textIn eukaryotic cells, mitochondria play the fundamental role of ATP production during the
process of oxidative phosphorylation (OXPHOS). However, these cytosolic organelles also
have several other important physiological functions, including sugar and fatty acid catabo-
lism, amino acid metabolism, buffering of the cytosolic calcium concentration (Rizzuto
et al., 2012), regulation and execution of different types of cell death (Galluzzi et al., 2012)
and arrangement of adaptive responses to perturbations of intracellular homeostasis (Liesa
and Shirihai, 2013). Furthermore, mitochondria are able to discharge a range of intracel-
lular signals including reactive oxygen species (ROS), mitochondrial DNA (mtDNA) and
specific proteins, thus operating as fundamental hubs of a wide array of signalling pathways
(Galluzzi et al., 2012)
Methods and models for functional studies on mtDNA mutations
No full textAfter 30 years of mitochondrial medicine, several models and methods for studying the pathogenic effects of mtDNA mutations have been developed. However, considering the difficulty to manipulate mtDNA, the possibility to obtain models for mitochondrial diseases remains challenging. Recently, the perspective to generate induced pluripotent stem cells from patients’ fibroblasts and differentiate them in specific cell populations or organoid has raised great interest for studying the molecular mechanisms of mitochondrial dysfunctions and for drug screening. Despite the technical hurdles, some animal models with mutations in mtDNA have been generated and represent valuable tools for the study of pathogenetic mechanisms and the test of new therapies. In parallel, biochemical methods for assessing mitochondrial function and efficiency are more and more sophisticated and developed on a small scale. Here, we summarize and discuss the different models and methods currently used to investigate the impact of mtDNA alterations on OXPHOS complexes function and structure
Use of bacterial photosynthetic vesicles to evaluate the effect of ionic liquids on the permeability of biological membranes
No full text: Ionic liquids (ILs) are salts composed of a combination of organic or inorganic cations and anions characterized by a low melting point, often below 100 °C. This property, together with an extremely low vapor pressure, low flammability and high thermal stability, makes them suitable for replacing canonical organic solvents, with a reduction of industrial activities impact on the environment. Although in the last decades the eco-compatibility of ILs has been extensively verified through toxicological tests performed on model organisms, a detailed understanding of the interaction of these compounds with biological membranes is far from being exhaustive. In this context, we have chosen to evaluate the effect of some ILs on native membranes by using chromatophores, photosynthetic vesicles that can be isolated from Rhodobacter capsulatus, a member of the purple non‐sulfur bacteria. Here, carotenoids associated with the light-harvesting complex II, act as endogenous spectral probes of the transmembrane electrical potential (ΔΨ). By measuring through time-resolved absorption spectroscopy the evolution of the carotenoid band shift induced by a single excitation of the photosynthetic reaction center, information on the ΔΨ dissipation due to ionic currents across the membrane can be obtained. We found that some ILs cause a rather fast dissipation of the transmembrane ΔΨ even at low concentrations, and that this behavior is dose-dependent. By using two different models to analyze the decay of the carotenoid signals, we attempted to interpret at a mechanistic level the marked increase of ionic permeability caused by specific ILs
An Article About Albertus C. Van Raalte, Author Unknown, Except for Parts Taken from an Article by Anna C. Post
No full textAn article about Albertus C. Van Raalte, author unknown, except for parts taken from an article by Anna C. Post. The author knew first generation persons in the Holland settlement and therefore, the article has some value.https://digitalcommons.hope.edu/vrp_1890s/1012/thumbnail.jp
The effects of idebenone on mitochondrial bioenergetics
No full textWe have studied the effects of idebenone on mitochondrial function in cybrids derived from one normal donor (HQB17) and one patient harboring the G3460A/MT-ND1 mutation of Leber's Hereditary Optic Neuropathy (RJ206); and in XTC.UC1 cells bearing a premature stop codon at aminoacid 101 of MT-ND1 that hampers complex I assembly. Addition of idebenone to HQB17 cells caused mitochondrial depolarization and NADH depletion, which were inhibited by cyclosporin (Cs) A and decylubiquinone, suggesting an involvement of the permeability transition pore (PTP). On the other hand, addition of dithiothreitol together with idebenone did not cause PTP opening and allowed maintenance of the mitochondrial membrane potential even in the presence of rotenone. Addition of dithiothreitol plus idebenone, or of idebenol, to HQB17, RJ206 and XTC.UC1 cells sustained membrane potential in intact cells and ATP synthesis in permeabilized cells even in the presence of rotenone and malonate, and restored a good level of coupled respiration in complex I-deficient XTC.UC1 cells. These findings demonstrate that idebenol can feed electrons at complex III. If the quinone is maintained in the reduced state, a task that in some cell types appears to be performed by dicoumarol-sensitive NAD(P)H:quinone oxidoreductase 1 [Haefeli et al. (2011) PLoS One 6, e17963], electron transfer to complex III may allow reoxidation of NADH in complex I deficiencies
Richardson, Barbauld, and the construction of an early modern fan club
No full textMPhilMuch has been written about the life and long works of the eighteenth century epistolary novelist, Samuel Richardson, but the prospect of his position as the first celebrity novelist – responsible for courting his own fame as well as initiating his own fan club – has largely been ignored. The body of manuscripts housed at the National Art Library in the Victoria and Albert Museum in London provides the modern scholar with evidence of the skeletal beginnings of an early fan club. This thesis aims to show how these manuscripts were turned into a saleable commodity by the publisher and entrepreneur Richard Phillips, while under the guiding hand of another, slightly later, literary celebrity, Anna Laetitia Barbauld. In order to restore Richardson’s reputation amongst a new nineteenth century audience, Barbauld was required to construct her own idea of him as an eighteenth century celebrity author, and in doing so the insecurities of a self-professed, apparently diffident man, are revealed. Barbauld’s capacious, but heavily edited selection of letters is analyzed in this thesis, providing ample evidence that Richardson’s correspondents were more than just eager letter writers. By using Barbauld’s biography of Richardson this thesis aims to show how she manipulates the genre of life writing in her construction of him.
This thesis offers an alternative reading of how the Richardson manuscripts are viewed, redefining them as not simply a collection of letters, but as a collective entity, deliberately selected and archived as evidence of an early modern fan club, and its celebrity managing director
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