Nijmegen, Netherlands
Nijmegen, Netherlands

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Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.82M | Year: 2013

The expanding diversification and specialization of knowledge and the growing complexity of contemporary research in translational research warrant the creation of cooperative multi-disciplinary networks including both basic and medically oriented expertise. This notion is especially true for Mitochondrial Medicine which aims at understanding the physiopathological mechanisms sharing the features of mitochondrial biology and represents an ideal platform for the training of young investigators who will develop a broad view of biomedical sciences working in such a multifaceted area of research. The project will create a network of 10 basic and translational laboratories (among which 2 SMEs) and 2 associated partners who will provide well established professional tools for training and dissemination. MEET will train 11 ESRs and 3 ERs supervised in their research by 15 mentors and by their collaborators. In addition, the 14 trainees will attend at least 1 advanced course in the genetic field, 1 complementary training course about public and private financial sources for R&D and Innovation projects and 1 or 2 selected technical workshops organized by the 10 partner laboratories. The cohesion of the research and teaching activities will be guaranteed by: monthly telematic meetings of, an international scientific Symposium specifically addressed to associations and foundations of patients and patients families in order to exchange the most up-to-date knowledge advances.By creating the critical mass of scientific excellence documented by the track records of the individual investigators, most of whom have worked together in the FP6 EUMITOCOMBAT project, MEET will combine the efforts of leading clinicians with those of more basic oriented groups and will have important implications for the comprehension and treatment of mitochondria-related pathologies


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2016 | Award Amount: 3.92M | Year: 2016

Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. The mitochondrial oxidative phosphorylation (OXPHOS) system, which produces the majority of cellular energy in the form of ATP, is controlled by two distinct genomes: the nuclear and the mitochondrial genome (mtDNA). Mutations in mitochondrial genes encoded by either genome could cause diseases affecting OXPHOS system, called mitochondrial diseases, whose prevalence has been estimated to be 1:8500. Moreover, dysfunction of mitochondrial OXPHOS system has emerged as a key factor in a myriad of common diseases, including neurodegenerative and metabolic disorders like Parkinsons and Alzheimers Disease, Type 2 Diabetes, and was linked to aging process. Despite all this, it is surprising that our understanding of the mechanisms governing the mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions unexplored. The basic machineries for mtDNA replication, mtDNA transcription and mitochondrial translation are known, but the regulation of these processes in response to metabolic demands is poorly understood. The complex nature of mitochondrial gene expression that relies on two different genomes calls for a multidisciplinary approach where different teams of researchers join forces. Studies in this area are not only of basic scientific interest but may also provide new avenues towards treatment of mitochondrial dysfunction in a variety of human diseases. The key aim of the REMIX Network is combine the skills of European research groups to provide strategic training of the next generation of scientists through a programme that will progress in the elucidation of the molecular mechanisms and pathways that regulate mitochondrial gene expression.


PubMed | Radboud Institute for Molecular Life science and Khondrion BV
Type: Journal Article | Journal: Nature protocols | Year: 2016

Mitochondria have a central role in cellular (patho)physiology, and they display a highly variable morphology that is probably coupled to their functional state. Here we present a protocol that allows unbiased and automated quantification of mitochondrial morphofunction (i.e., morphology and membrane potential), cellular parameters (size, confluence) and nuclear parameters (number, morphology) in intact living primary human skin fibroblasts (PHSFs). Cells are cultured in 96-well plates and stained with tetramethyl rhodamine methyl ester (TMRM), calcein-AM (acetoxy-methyl ester) and Hoechst 33258. Next, multispectral fluorescence images are acquired using automated microscopy and processed to extract 44 descriptors. Subsequently, the descriptor data are subjected to a quality control (QC) algorithm based upon principal component analysis (PCA) and interpreted using univariate, bivariate and multivariate analysis. The protocol requires a time investment of 4 h distributed over 2 d. Although it is specifically developed for PHSFs, which are widely used in preclinical research, the protocol is portable to other cell types and can be scaled up for implementation in high-content screening.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-02-2015 | Award Amount: 6.00M | Year: 2015

The overall objective of this project is to identify novel drug candidates capable of slowing down the progression of neurodegeneration in the subset of Parkinsons disease (PD) patients with overt mitochondrial dysfunction. Multi-modal phenotypic characterisation of cohorts of monogenic PD patients with overt mitochondrial dysfunction will be used as an anchor for the discovery of two extreme cohorts of idiopathic PD patients: with and without detectable mitochondrial dysfunction. A suite of personalised in vitro, in vivo, and in silico models will be generated using induced pluripotent stem cells (iPSCs) from selected subjects and controls. An industrial quality 3D microfluidic cell culture product, specifically designed for the culture of iPSC-derived dopaminergic neurons, will be developed for use in a morphological and bioanalytical screen for lead compounds reduce mitochondrial dysfunction. By monitoring motor behaviour and in situ striatal neurochemistry at high temporal resolution, the in vivo response to lead compounds will be characterised in humanised mouse models with striatally transplants of iPSC-derived dopaminergic neurons derived from PD patients. Personalised computational models of dopaminergic neuronal metabolism and mitochondrial morphology will be developed. These in silico models will be used to accelerate drug development by prioritising pathways for metabolomic assay optimisation, stratifying idiopathic PD patients by degree of mitochondrial dysfunction, predicting new new targets to reduce mitochondrial dysfunction and mechanistic interpretation in vitro and in vivo experimental results. SysMedPD unites a highly experienced multidisciplinary consortium in an ambitious project to develop and apply a systems biomedicine approach to preclinically identify candidate neuroprotectants, for the estimated 1-2 million people worldwide who suffer from PD with mitochondrial dysfunction.


Foriel S.,Khondrion BV | Willems P.,Radboud University Nijmegen | Smeitink J.,Khondrion BV | Smeitink J.,Radboud University Nijmegen | And 2 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2015

While often presented as a single entity, mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. Among them, defects in the process of oxidative phosphorylation are the most prevalent. Despite intense research efforts, patients are still without effective treatment. An important part of the development of new therapeutics relies on predictive models of the pathology in order to assess their therapeutic potential. Since mitochondrial diseases are a heterogeneous group of progressive multisystemic disorders that can affect any organ at any time, the development of various in vivo models for the different diseases-associated genes defects will accelerate the search for effective therapeutics. Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. © 2015 Elsevier Ltd. All rights reserved.


Iannetti E.F.,Khondrion BV | Willems P.H.G.M.,Khondrion BV | Willems P.H.G.M.,Radboud University Nijmegen | Pellegrini M.,Khondrion BV | And 6 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2015

Mitochondria are double membrane organelles involved in various key cellular processes. Governed by dedicated protein machinery, mitochondria move and continuously fuse and divide. These "mitochondrial dynamics" are bi-directionally linked to mitochondrial and cell functional state in space and time. Due to the action of the electron transport chain (ETC), the mitochondrial inner membrane displays a inside-negative membrane potential (Δψ). The latter is considered a functional readout of mitochondrial "health" and required to sustain normal mitochondrial ATP production and mitochondrial fusion. During the last decade, live-cell microscopy strategies were developed for simultaneous quantification of Δψ and mitochondrial morphology. This revealed that ETC dysfunction, changes in Δψ and aberrations in mitochondrial structure often occur in parallel, suggesting they are linked potential targets for therapeutic intervention. Here we discuss how combining high-content and high-throughput strategies can be used for analysis of genetic and/or drug-induced effects at the level of individual organelles, cells and cell populations. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. © 2015 Elsevier Ltd. All rights reserved.


PubMed | Radboud University Nijmegen and Khondrion BV
Type: | Journal: The international journal of biochemistry & cell biology | Year: 2015

Mitochondria are double membrane organelles involved in various key cellular processes. Governed by dedicated protein machinery, mitochondria move and continuously fuse and divide. These mitochondrial dynamics are bi-directionally linked to mitochondrial and cell functional state in space and time. Due to the action of the electron transport chain (ETC), the mitochondrial inner membrane displays a inside-negative membrane potential (). The latter is considered a functional readout of mitochondrial health and required to sustain normal mitochondrial ATP production and mitochondrial fusion. During the last decade, live-cell microscopy strategies were developed for simultaneous quantification of and mitochondrial morphology. This revealed that ETC dysfunction, changes in and aberrations in mitochondrial structure often occur in parallel, suggesting they are linked potential targets for therapeutic intervention. Here we discuss how combining high-content and high-throughput strategies can be used for analysis of genetic and/or drug-induced effects at the level of individual organelles, cells and cell populations. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.


PubMed | Donders Institute for Brain, Radboud University Nijmegen and Khondrion BV
Type: | Journal: The international journal of biochemistry & cell biology | Year: 2015

While often presented as a single entity, mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. Among them, defects in the process of oxidative phosphorylation are the most prevalent. Despite intense research efforts, patients are still without effective treatment. An important part of the development of new therapeutics relies on predictive models of the pathology in order to assess their therapeutic potential. Since mitochondrial diseases are a heterogeneous group of progressive multisystemic disorders that can affect any organ at any time, the development of various in vivo models for the different diseases-associated genes defects will accelerate the search for effective therapeutics. Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

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