Koopman 2013 Abstract MiP2013

Koopman WJH (2013) Developing novel treatment strategies for mitochondrial disease. Mitochondr Physiol Network 18.08.

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MiP2013, Book of Abstracts Open Access

Koopman WJ (2013)

Event: MiPNet18.08_MiP2013

The OXPHOS system consists of 5 multi-subunit Complexes (CI to CV) that contain 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNA-encoded OXPHOS assembly factors (chaperones), of which 35 are currently identified. OXPHOS and mitochondrial dysfunction are not only associated with relatively rare monogenic mitochondrial disorders but also observed during more common pathologic conditions, such as Alzheimer’s, Huntington’s and Parkinson’s disease, cancer, cardiac disease, diabetes, epilepsy, and obesity. In addition, a progressive decline in the expression of mitochondrial genes is observed during normal human aging and mitochondrial function is inhibited by environmental toxins and frequently used drugs. Mutations in OXPHOS structural genes are associated with neurodegenerative diseases including Leigh Syndrome, which is probably the most classical OXPHOS disease during early childhood. Our research focuses on gaining a quantitative mechanistic understanding of mitochondrial (patho)physiology at the (sub)cellular level in OXPHOS disorders. To this end, the following scientific questions are addressed: (i) How are mitochondrial (ultra)structure and cell metabolic function connected during mitochondrial (dys)function, (ii) How do cells adapt to mitochondrial dysfunction? (iii) How can mitochondrial dysfunction be mitigated at the cellular and organismal level? To this end, protein-based and chemical fluorescent reporter molecules are introduced in healthy and patient-derived primary cells, as well as established cell lines to allow analysis of mechanistic aspects. (Patho)physiology is then investigated using biochemical and molecular cloning techniques, high-resolution respirometry, state-of-the-art quantitative (sub)cellular life cell microscopy, single-molecule spectroscopy, mathematical modelling, image processing, data mining and machine learning techniques. Using this strategy, we have developed a collection of novel small molecules that are currently investigated in animal models of mitochondrial deficiency.

• O2k-Network Lab: NL Nijmegen Koopman WJ

Labels: MiParea: Respiration, mt-Structure;fission;fusion, mtDNA;mt-genetics, nDNA;cell genetics, Genetic knockout;overexpression, mt-Medicine  Pathology: Inherited 

Tissue;cell: Other cell lines 

HRR: Oxygraph-2k 

MiP2013 

Affiliations and author contributions

Dept of Biochemistry, Radboud University Medical Centre, Nijmegen, The Netherlands. - Email: [email protected]

References

1. Nijtmans LGJ, Rodenburg RJ, Szklarcyk R, Willems PHGM, Koopman WJH, Smeitink JAM (2013) Assembly of OXPHOS complexes. Cell Metabolism (in press).
2. Willems, P.H.G.M., Wanschers, B., Esseling, J., Szklarzyk, R., Kudla, U., Duarte I., Nooteboom, M., Forkink, M., Swarts H, Gloerich J, Nijtmans LJ, Koopman WJH, Huynen M (2013) BOLA1 is an aerobic protein that prevents mitochondrial morphology changes induced by glutathione depletion. Antioxidants and redox signaling therapeutics 18:129-138.
3. Koopman WJH, Distelmaier F, Smeitink JAM, Willems PHGM (2013) OXPHOS mutations and neurodegeneration. EMBO J 32: 9-29.
4. Distelmaier F, Valsecchi F, Forkink M, Van Emst-de Vries S, Swarts H, Rodenburg R, Verwiel E, Smeitink J, Willems PHGM, Koopman WJH (2012) Trolox-sensitive ROS regulate mitochondrial morphology, oxidative phosphorylation and cytosolic calcium handling in healthy cells. Antioxidants and redox signaling 17: 1657-1669.
5. Koopman WJH, Willems PHGM, Smeitink JAM (2012) Monogenic mitochondrial disorders. N Eng J Med 366: 1132-1141.
6. Dieteren CEJ, Gielen SCAM, Nijtmans LGJ, Smeitink JAM, Swarts HG, Brock R, Willems PHGM, Koopman WJH (2011) Solute diffusion is hindered in the mitochondrial matrix. Proc Natl Acad Sci USA 108: 8657-8662.
7. Koopman WJH, Nijtmans LG, Dieteren CEJ, Roestenberg P, Valsecchi F, Smeitink JAM, Willems PHGM (2010) Mammalian mitochondrial Complex I: Biogenesis, regulation and reactive oxygen species generation. Antioxidants Redox Signaling 12:1431-1470.
8. Distelmaier F, Koopman WJH, Van den Heuvel LW, Rodenburg RJ, Mayatepek E, Willems PHGM, Smeitink JAM (2009) Mitochondrial Complex I deficiency: from organelle dysfunction to clinical disease. Brain 132: 833-842.
9. Eisenberg I, Noversthern N, Itzaki Z, Becker-Cohen M, Sadeh M, Willems PHGM, Friedman N, Koopman WJH, Mitrani-Rosenbaum S (2008) Mitochondrial processes are impaired in hereditary inclusion body myopathy. Hum Mol Genet 17: 3663-3674.