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)