Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Human Molecular Genetics 22.16 (2013): 3296-3305 is available online at http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=23604518X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous system characterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA. In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. We have formerly shown that an excess of the VLCFA C26:0 induces oxidative damage, which underlies the axonal degeneration exhibited by the Abcd1(-) mice. In the present study, we sought to investigate the noxious effects of C26:0 on mitochondria function. Our data indicate that in X-ALD patients' fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) triggering mitochondrial ROS production from electron transport chain complexes. This correlates with impaired complex V phosphorylative activity, as visualized by high-resolution respirometry on spinal cord slices of Abcd1(-) mice. Further, we identified a marked oxidation of key OXPHOS system subunits in Abcd1(-) mouse spinal cords at presymptomatic stages. Altogether, our results illustrate some of the mechanistic intricacies by which the excess of a fatty acid targeted to peroxisomes activates a deleterious process of oxidative damage to mitochondria, leading to a multifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALDThis study was supported by grants from the European Commission (FP7-241622), the European Leukodystrophy Association (ELA2009-036C5; ELA2008-040C4), the Spanish Institute for Health Carlos III (FIS PI080991 and FIS PI11/01043), the Autonomous Government of Catalonia (2009SGR85) to A.P. and the Spanish Institute for Health Carlos III (Miguel Servet program CP11/00080) to S.F. The CIBER on Rare Diseases (CIBERER) is an initiative of the ISCIII. The study was developed under the COST action BM0604 (to A.P.). J.L.-E. was a fellow of the Department of Education, Universities and Research of the Basque Country Government (BFI07.126). S.F. was a fellow of the European Leukodystrophy Association (ELA 2010-020F1). The studies conducted at the Department of Experimental Medicine were supported in part by R&D grants from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI), the Spanish Ministry of Health (PI11/1532), the Autonomous Government of Catalonia (2009SGR735), the ‘La Caixa’ Foundation and COST B35 Action of the European Union. D.C. is a fellow from the Spanish Ministry of Health (FI08-00707). The studies conducted at the Department of Biochemistry and Molecular Biology, University of Barcelona, were supported by grants SAF2008-01896 and SAF2011-23636 from the Spanish Ministry of Science and Innovatio

The environmental and social footprint of the university of the Basque Country UPV/EHU

This work has calculated the organisational environmental and social footprint of the University of the Basque Country (UPV/EHU) in 2016. First, input and output data flows of the UPV/EHU activity were collected. Next, the environmental and social impacts of the academic activity were modelled, using the Ecoinvent 3.3 database with the PSILCA-based Soca v1 module in openLCA software. In order to evaluate the environmental impacts, CML and ReCiPe LCIA methods were used. The Social Impact Weighting Method was adjusted for the assessment of specific social impacts. The modelling has identified some hotspots in the organisation. The contribution of transport (8,900 km per user, annually) is close to 60% in most of the environmental impacts considered. The life cycle of computers stands out among the impacts derived from the consumption of material products. More than half of environmental impacts are located outside the Basque Country. This work has also made it possible to estimate some of the impacts of the organisational social footprint, such as accidents at work, only some of which occur at the UPV/EHU. Traces of child labour and illiteracy have also been detected in the social footprint that supports the activity of the UPV/EHU. Some of the social and environmental impacts analysed are not directly generated by the UPV/EHU, but they all demand attention and co-responsibility. Based on the modelling performed, this work explores alternative scenarios and recommends some improvement actions which may reduce (in some cases over 30%) the environmental and social impacts of the UPV/EHU's activity. These scenarios and improvement actions will feed a process with stakeholders in the UPV/ EHU based on the Multi-criteria Decision Analysis (MCDA) methodology.To the Sustainability Directorate and the Educational Advisory Service, both belonging to the Vice-Chancellor's Office for Innovation, Social Commitment and Social Action of the University of the Basque Country UPV/EHU, in the context of the Campus Bizia Lab programme (2017/18, 18/19 and 19/20 calls) for the financing of the EHU-Aztarna project. This research has also been supported by 'Ekopol: Iraunkortasunerako Bideak' research group, recognised by the Basque Government (IT1365-19) and the University of the Basque Country UPV/EHU (GIC-18/22)

Development of steels reinforced with primary carbides by conventional liquid metallurgical process

The improvements that could be obtained in the properties of cast structural alloys through the reinforcing its matrix with hard, microscopic and dispersed ceramic particles (TiC, VC, NbC), are accepted and recognized. In this sense, the development of a liquid metallurgy process enabling the reinforcement by means of the addition of the ceramic material to the molten metal in the melting furnace would become an important advance in the metallic materials field. Nevertheless, these ceramic products are prone to the coalescence and have pour wettability into molten baths as steel, superalloys, etc., so that the resulting operation yield and the subsesquent property improvement are very low. In order to solve these disadvantages, we have developed a liquid metallurgical process allowing to make steel products with a composed microstructure of martensitic matrix and discrete primary carbides (MoTi)C metallurgically embedded in rt. This process includes the following fundamental steps: previous preparation of the material of reinforcement, in this case of Fe(MoTi)C type. melting of the steel bath by means of conventional electric furnaces. addition of the carbide particules material to the molten steel bath, pouring, solidification and heat treatment

New steelmaking process by combining natural gas oxycombustion and plasma technology

A new research project was made in a pilot-plant to study the possibilities of extending oxygas rotary smelting technology to the steelmaking sector in which electrical induction furnaces and electric arc furnaces have traditionally been used. The steelmaking process has been developed by combining two different technologies: the oxygas rotary furnace and the ladle with plasma torch. Technological benefit is made of both oxycombustion and plasma as energy sources in the field of steel melting and refining processes. Oxycombustion technology offers a further advantage, i.e., natural gas/pure oxygen combustion can take place in a stoichiometric, reducing (lack of oxygen) or oxidizing (excess of oxygen) form. The new steelmaking process is technically viable, as it enables liquid steel of good metallurgic quality to be produced from raw materials of poor quality and low cost.Peer reviewe

Selfpropagating high temperature synthesis (SHS) of the Fe(TiMo)C masteralloy using ferroalloys

Titanium monocarbide TiC is very hard, stable both at high and low temperatures and relatively easy to synthesize from its constituent elements by SHS. Nevertheless, it is difficult to use, as alloying element, in the reinforcement of steels manufactured by liquid metallurgy due to its low wettability by molten steel. To achieve this purpose and due to its better wettability, it is more appropriate to use a master alloy formed by the complex carbide (TiMo)C bonded in Fe. The simplest and most economic way to fabricate such a master alloy Fe(TiMo)C is, again, by SHS, with the added advantage that it can be manufactured using the commercial ferroalloys FeTi and FeMo instead of the individual elements Fe, Ti and Mo. In this work, we describe such a process as well as the characteristics of the master alloy obtained.Peer reviewe

Development of high pressure die casting dies with internal refrigeration and sensors with reinforced cast steel

High Pressure Die Casting (HPDC) dies are nowadays manufactured with high quality forged steels, as the H11 and H13 steels. Cavities are made by electrical discharge machining (EDM) or by high speed milling, with a high percentage of metal loss in these operations. The average life of a standard aluminium HPDC die is about 125.000 injections, and the total price of tooling can represent around up to the 30% of the total price of the finished part. Refrigeration circuits have simple configurations, due to that they are commonly produced by drilling the die with straight holes connected between them. They are also limitations in the distances and minimum diameters of holes. Sensors are also placed where the geometry of the die permits an easy machining of location holes. In order to obtain complex figures, several new rapid prototyping methods have been developed, including sometimes customized internal circuits, as for example the laser sintering, and also for decreasing the die lead time (around 12 weeks for a standard die). However, there is a clear limitation in the life of the die produced by this technique, from several parts to thousands. A new method to obtain directly semi-finished high pressure die casting dies in a steel of higher mechanical properties and with the refrigeration circuits and sensors embedded into it is described in this paper. The method consists in produce a molten steel alloy with micro-nano special ceramic particles inserted in it, and cast the composite material in sand moulds of the desired geometry having placed properly designed refrigeration and sensor circuits. The resultant solidified near-net shape die, of steel reinforced with hard and refractory ceramics and with the cooling tubes and sensors embedded into it, is then heat treated and finished, having a use-life and a productivity about 50% and 10% higher, respectively.Peer reviewe

Desarrollo de aceros reforzados con carburos primarios vía metalurgia líquida

The steel reinforcement by means of the addition of primary carbides via liquid metallurgy needs to fulfil two essential requirements to be technically viable: the development of a solid reinforcing product which is appropriate to be mixed with the steel and the optimisation of the metallurgic addition of these reinforcing particles into the liquid steel. Besides, the improvement of the reinforced alloy characteristics is directly related to the particles' nature of reinforcing particles, their homogeneous and uniform distribution in the matrix and their size and morphology. The manufacture of these carbides by SHS ('Self propagating High temperature Synthesis') and their addition before steel is poured into moulds allows achieving the above-mentioned conditions.Peer reviewe