NeMo’s overall goal is To understand the role of mitochondria in health and disease, and to improve the quality of life and treatment of humans with mitochondrial dysfunction (MD). NeMo bridges research and education on mitochondrial (patho)biology, to improve medicines and care on the following MD-associated disorders:
- Genetic Mitochondrial Diseases (GMDs)
- Ageing & Ageing-related dysfunction
- Antibiotics & AntiGMD (cross-kingdom approaches)
Collaborations within the ACE
Project title: Comparing metabolism of IDH (isocytrate dehydrogenase) wild-type versus IDH mutant glioblastoma cells
Collaborators: Martine Lamfers, Cassandra Verheul, Pier Mastroberardino, Eelke Bos, Sieger Leenstra
Project title: Characterizing metabolic changes upon therapy resistance of glioblastoma and development of non-invasive imaging to monitor metabolic changes.
Collaborators: Jeroen de Vrij, Pier Mastroberardino, Sieger Leenstra:
Project title: mitochondrial dysfunction in aneurysmal disease
Collaborators: Chiara Milanese, Pier Mastroberardino, Pluijm
Project title: prematurely aging DNA repair deficient mouse models, cardio-vascular aging, aneurism, imaging tools
Collaborators: Ingrid van der Pluijm, Jeroen Essers
Project title: development and testing of cellular and molecular imaging tools in living animals, necroptosis
Collaborators: Clemens Lowik
Collaborations with other ACE initiatives (underlined names identify participants in the NeMo ACE)
Project title: Pompe disease and other lysosomal storage disorders
Collaborators: Esther Brusse, Pieter van Doorn, Ans van der Ploeg, Nadine van der Beek, Pim Pijnappel, Gerben Schaaf
ACE involved: Lysosomal and Metabolic Diseases
Project title: immune-myopathies, intravenous immunoglobulin (IVIg) treatment
Collaborators: Esther Brusse, Pieter van Doorn, Martin van Hagen,
ACE involved: Allergic Diseases
Project title: inflammatory neuropathies (Guillain-Barre syndrome and CIDP)
Collaborators: Pieter A van Doorn, Bart Jacobs, Maarten Titulaer, Peter Sillevis Smitt
ACE involved: Neuroinflammation
Project title: chronic idiopathic polyneuropathy
Collaborators: Pieter A van Doorn, Arfan Ikram
ACE involved: Epidemiology/Population neuroscience
Project title: MR thoracic imaging in Pompe disease and other neuromuscular disorders
Collaborators: Pieter A van Doorn, Harm Tiddens, Marleen de Bruijne
ACE involved: Quantitative imaging
Project title: cerebellar dysfunction and small fiber neuropathy
Collaborators: Pieter A van Doorn, Esther Brusse, Chris de Zeeuw
ACE involved: Brain motion
Project title: To study the effects on tumor metabolism on the effectivity of oncolytic virotherapy
Collaborators: Martine Lamfers, Jeroen de Vrij, Bernadette van den Hoogen
ACE involved: Tumor immunology and Immune Therapy
Project title: To identify novel metabole-targeting drugs for treatment of glioma
Collaborators: Martine Lamfers, Jeroen de Vrij, Sieger Leenstra
ACE involved: Adult and Pediatric Brain Tumor
Project title: Use of mitochondrial oxygen consumption as a quality measure of donor livers
Collaborators: Bert Mik, Harold Raat, J. de Jonge
ACE involved: Hepato-Pancreato-Biliary diseases
Project title: Optimizing working space in laparoscopy
Collaborators: Bert Mik, Harold Raat, John Vlot
ACE involved: Congenital Anatomical Malformations
Project title: Hepatitis E virus replication in relation to mitochondrial function
Collaborators: Bert Mik, Harold Raat, Quiwei Pan
ACE involved: Stem Cells & Organoids in Personalized and Regenerative medicine (SCORE)
Project title: Bioenergetics characterization of a patient carrrying a new mutations in teh gene TMX2
Collaborators: Chiara Milanese, Pier G Mastroberardino, Maria Grazia Verheijn-Mancini
ACE involved: Neuro-developmental disorders (Encore)
Collaborators: S. Sleijfer, Pauline Mendelaar, J.W.M. Martens
ACE involved: Breast Cancer
Collaborators: Esther Brusse, Dr Ruud Selles, prof Chris de Zeeuw, Dr Maarten Titulaer, dr Vincenzo Bonifati
ACE involved: Brain Motion
The Hoeijmakers team investigates the molecular mechanism of DNA repair and its biological and clinical impact. For this we adopt an integral approach ranging from molecule to patient. Since DNA damage lies at the basis of aging (-related diseases) and cancer we have intensive collaborations with research groups in the following ACEs:
- The ACE Research Center for Sustaining Health (CRSH)
- The ACE Genome Repair Targeted Cancer Treatments (GRTCT)
At the technical level we have longstanding, intimate collaborations with members of ACE Molecular and Cellular Imaging (MCI): e.g. Adriaan Houtsmuller, Gert van Capelle.
Previous activities: in light of the drastic changes in the ACE, these will be reviewed and reassessed in the near future
Non-invasive monitoring of mitochondrial respiration for guiding diagnosis and treatment. EMC (Dr. EG Mik, Dr. NJH Raat (Dept. Anesthesiology), IFM de Coo (Dept. Neurology)), Radboud UMC, Nijmegen (Prof. M Kox, Intensive Care Unit, Radboud UMC, Nijmegen), Centre for Human Drug Research, Leiden (Prof. G. Groeneveld), Center for Clinical Transfusion Research at Sanquin Research / LUMC (Prof A van der Bom), Netherlands Metabolomics Centre / University Leiden (Prof T Hankemeijer)
Development of gene and cell therapy for mitochondrial diseases. EMC (IFM de Coo (Dept Neurology), J de Vrij (Dept Neurosurgery)), LUMC, Dept Molecular Cell Biology - Virus and Stem Cell Biology unit (Prof RC Hoeben) DNA Repair Mutations and Cellular Aging (including mitochondrial mechanisms). National Institute of Health (NIH) consortium. Includes EMC (WP Vermeij, JHJ Hoeijmakers), PPG grant NIH/NIA: 2014-2019.
Mitochondria as therapeutic target for cardiovascular disease. EMC (I van der Pluijm, PG Mastroberardino, R Kanaar, J. Essers (Dept Molecular Genetics), A Ijpma (Dept Bio Informatics), JA Demmers (Proteomics Center)), McGill University (EC Davis), University of Tsukuba (Hiromi Yanagisawa), Johns Hopkins University School of Medicine (Harry C. Dietz)
Mitochondrial DNA in cancer: mtDNA level and/or mutations determine oncogenesis and therapy resistance? EMC (Dr. J de Vrij, Prof. S Leenstra (Dept Neurosurgery), Prof. SS Sleijfer (Dept. Internal Oncology)), MUMC+ (Prof. HJM Smeets) Access and dual manipulation of conserved prokaryotic targets against infectious and mitochondrial diseases. EMC (Dr. WH Goessens, Dr. JP Hays), University of Leeds, UK, InhibOx Ltd, London, UK, Latvian Institute of Organic Synthesis, Riga, Latvia
Due to the drastic changes in the NeMo ACE, its contribution to education will be reviewed and reassessed in the near future. Thus far, however, it includes the following activities:
- BSc / MSc for Medical curriculum, including courses on "Mitochondria and Metabolism" and "Glucose homeostasis"
- BSc / MSc for Clinical Technology curriculum, including minor on "Systematic review Gene/Cell technology"
- BSc / MSc courses and Research Masters for Molecular Medicine and Nanobiology curriculum
- Education within the MolMed research school
- Minor Genetics in Society (EUR)
- Resident education - Neurology, Pediatrics and Clinical Genetics
- Tutoring, lecturing, supervising PhD students (currently 8, 3 from outside NL)
- Participation in educational committee Vereniging Klinisch Genetische Laboratoriumdiagnostiek
- Post-doctoral courses, hands-on workshops etc.
- Netherlands School for Mitochondrial Medicine (combined initiative Erasmus MC, MUMC+, Radboud UMC)
In addition, Pier Mastroberardino is establishing a new joint Master program between the Erasmus MC and the Rotterdam School of Management (RSM) focused on Medical Business and Innovation. NeMo is perfectly suited to be involved in this project and PGM will operate in this direction.
NeMo also aims at the establishment of an educational program around the theme "Mitochondrial disorders - from bedside to bench and back". Taking GMD patients at NeMo's outpatient clinic as starting point (neurological analyses, MRI imaging, etc.), the participants will "travel the modern route of personalized treatment of rare diseases". Sequentially, insights are obtained on diagnostics (genetic and biochemical), on personalized (gene) therapy development, and finally on implementation aspects of novel therapies in the clinic. This includes financial/cost benefit aspects (participation EUR- Institute for Medical Technology Assessment).
Societal Relevance to Research, Education and Patient Care
Nemo has a strong commitment to inform the general public and patient organizations about the scientific progress. This will be achieved by a dedicated website with educational information (Mitochondrialmedicine.org, online from September 2016), meetings with patient organizations and teaming with funding organizations. In collaboration with the VKS (Volwassenen, Kinderen en Stofwisselingsziekten) a national "kenniskaart" and several "zorgpaden" have been described and published. Guidelines have been developed for
- National guideline for mental retardation,
- Counseling by Genome Wide Detection - CNV diagnostics,
- the European SARA Age-validation Trial in children, and
- GMD patients, allowing for the first time the possibility to study the natural history of these disorders in a structured way.
A patent on mtDNA variants has been filed and a start-up company established (DNAMito). Nemo will participate in the training of (bio)medical students and in postacademic training programmes for neurologists and clinical geneticists. Based on genetic analysis, prevention of severe disease manifestations and in some cases life-saving interventions have been achieved (treatment with biotin and thiamin).
Finding new genetic causes will further extend this possibility of personalized treatment. Based on the genetic profiling, patients or their parents will have options to prevent the transmission to their offspring.
Viability of Research, Education and Patient Care
Viability of research is based on earning power, papers published and PhD students, who have finished their thesis. Nemo is doing extremely well with competitive funding of >8M€, 21 PhD students and >100 papers in the last 15 years.
Exchange of scientists from Rotterdam and Maastricht with the United Mitochondrial Disease Foundation (UMDF) promoted the establishment of the "Mitochondrial Disease Sequence Data Resource (MSeqDR)": a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities.
We facilitate further use of search-tools and deposition of data. This is a unique and stimulating example of collaboration with American and European scientist with a major contribution of the NeMo researchers. NeMo has extensive (inter)national connections and has shared publications with scientist that are top-ranked in mitochondrial research (e.g. evidenced by bibliometric analysis). NeMo will establish an organization structure that actively identifies talents and stimulates talent development. Multiple post-docs and PhD students have participated in exchange programs with the USA.
Key and relevant publications of the last five years
- Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Gerards M, Kamps R, van Oevelen J, Boesten I, Jongen E, de Koning B, Scholte HR, de Angst I, Schoonderwoerd K, Sefiani A, Ratbi I, Coppieters W, Karim L, de Coo R, van den Bosch B, Smeets H. Brain. 2013 Mar;136(Pt 3):882-90.
- A multi-center comparison of diagnostic methods for the biochemical evaluation of suspected mitochondrial disorders Rodenburg RJ, Schoonderwoerd GC, Tiranti V, Taylor RW, Rötig A, Valente L, Invernizzi F, Chretien D, He L, Backx GP, Janssen KJ, Chinnery PF, Smeets HJ, de Coo IF*, van den Heuvel LP*. Mitochondrion. 2013 Jan;13(1):36-43.
- Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. – PMID 26948435 - 2016;388:717-27
- Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease. Sepe S, Milanese C, Gabriels S, Derks KW, Payan-Gomez C, van IJcken WF, Rijksen YM, Nigg AL, Moreno S, Cerri S, Blandini F, Hoeijmakers JH, Mastroberardino PG. Cell Rep. 2016 May 31;15(9):1866-75.
- Simultaneous Whole Mitochondrial Genome Sequencing with Short Overlapping Amplicons Suitable for Degraded DNA Using the Ion Torrent Personal Genome Machine. Chaitanya L, Ralf A, van Oven M, Kupiec T, Chang J, Lagacé R, Kayser M. Hum Mutat. 2015 Dec;36(12):1236-47.
- Non-invasive monitoring of mitochondrial oxygenation and respiration in critical illness using a novel technique. Harms FA, Bodmer SI, Raat NJ, Mik EG. Crit Care. 2015 Sep 22;19:343.
- Mitochondrial DNA content in breast cancer: Impact on in vitro and in vivo phenotype and patient prognosis. Weerts MJ, Sieuwerts AM, Smid M, Look MP, Foekens JA, Sleijfer S, Martens JW. Oncotarget. 2016 Apr 11. doi: 10.18632/oncotarget.8688
- Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation. - PMID 29931197 - van der Pluijm I, Burger J, van Heijningen PM, IJpma A, van Vliet N, Milanese C, Schoonderwoerd K, Sluiter W, Ringuette LJ, Dekkers DHW, Que I, Kaijzel EL, Te Riet L, MacFarlane E, Das D, van der Linden R, Vermeij M, Demmers JA, Mastroberardino PG, Davis EC, Yanagisawa H, Dietz H, Kanaar R, Essers J. - Cardiovasc Res. 2018 Jun 21
- Restricted diet delays accelerated aging and genomic stress in DNA repair deficient mice. – PMID 27556946 - W.P. Vermeij, M.E.T. Dollé, E. Reiling, D. Jaarsma, C. Payan-Gomez, C.R. Bombardieri, H. Wu, A.J.M. Roks, S.M. Botter, B.C. van der Eerden, S.A.Youssef, R.V. Kuiper, B. Nagarajah, C.T. van Oostrom, R.M.C. Brandt, S. Barnhoorn, S. Imholz, J.L.A. Pennings, A. de Bruin, Á. Gyenis, J. Pothof, J. Vijg, H. van Steeg and J.H.J. Hoeijmakers. Nature 537, 427-431
PhD theses of the last five years
- Towards non‐invasive monitoring of mitochondrial function – Dr. FA Harms, 2014 (Dr. EG Mik)
- Imaging and phenotypical variation in Pompe disease – Dr. SCA Wens, 2016 (Prof. PA van Doorn)
- Duchenne from the 3rd Decade: Aspects of functioning and quality of life of adults with Duchenne muscular dystrophy – Dr. RF Pangalila, 2016 (Prof. HJ Stam)
- Approaches to Dissect the Complex Genetic Architecture of Common Traits – Dr. MV Struchalin, 2013 (Prof. M Kayser)
- Neuromuscular imaging and phenotypical variation in Pompe disease. - S.C.A. Wens. - Erasmus University Rotterdam, 18 May 2016
- Modeling of Malignant Glioma and Investigations into Novel Treatments – Dr. RK Balvers, 2015 (Prof. S Leenstra)
- Prevalence, risk factors and consequences of chronic polyneuropathy. - R. Hanewinckel. - The Rotterdam Study. Erasmus University Rotterdam, 20 June 2017 (Prof. van Doorn)
- Peripheral Neuropathy outcome measures Standardization (PeriNomS) study part 2: Getting consensus. - E.K. Vanhoutte - University Maastricht , 13 March 2015 (Prof. van Doorn)
- Ionizing radiation, DNA damage response and cancer therapy resistance - Serena Bruens - 7-2-2018 (Prof. Jan H. Hoeijmakers)
- GBS and CIDP spectrum and IVIg treatment - K. Kuitwaard - Erasmus University Rotterdam, 18 June 2018 (Prof. van Doorn)