MITOCHONDRIAL DYNAMICS

Towards a quantitative understanding of mitochondrial dynamics and function in the living cell

At the (sub)cellular level, metabolism is thought to be linked to dynamic alterations in mitochondrial motility, position, structure, mass and function. When mitochondrial dynamics is disturbed, for instance during pathology, alterations in cellular signal processing and effector (dis)regulation occurs.

My group focuses on gaining a quantitative and mechanistic understanding of the coupling between mitochondrial dynamics and function, and its regulation, at the (sub)cellular level. To this end we bring chemical and proteinaceous reporter molecules inside living cells and perturb mitochondrial dynamics and/or function by genetic and/or exogenous means. In addition to classical biochemical techniques, the effects of these manoeuvres are studied using: 

- Mitochondrial dynamics (see example below)

- Submitochondrial fluorescence recovery after photobleaching (FRAP) analysis

- Non-linear signal transduction cascades (multidimensional)

- Small molecule diffusion, binding and reaction (multidimensional)

This ‘not-images-but-numbers’ approach will provide a much needed quantitative view in this research field. It is expected that the obtained results will not only contribute to the fundamental understanding of mitochondrial and cellular (patho)physiology, but also to the development of therapeutics for the many human  disorders in which mitochondrial dynamics is disturbed including inherited mitochondrial disorders, metabolic syndrome, diabetes, cancer and aging.

Contact
Werner J.H. Koopman, PhD.
Dept. of Biochemistry (286)
Nijmegen Centre for Molecular Life Sciences
Radboud University Nijmegen Medical Centre
P.O. Box 9101, 6500HB Nijmegen
The Netherlands
Tel: +31-24-3614589
Fax: +31-24-3616413
E-mail: W.Koopman@ncmls.ru.nl

Technical assistance
Ing. Herman G. Swarts
Ing. Sjenet E. van Emst-de Vries

 

Selected key publications

Koopman, W.J.H., Scheenen, W.J.J.M., Errington, R.J., Willems, P.H.G.M., Bindels, R.J.M., Roubos, E.W., Jenks, B.G. (2001) Membrane-initiated Ca2+ signals are reshaped during propagation to subcelular regions. Biophys. J. 81, 57-65.

De Groof, A.J.C., Fransen, J.A.M., Errington, R.J., Willems, P.H.G.M., Wieringa, B. and Koopman, W.J.H. (2002) The creatine kinase system is essential for optimal refill of the sarcoplasmic reticulum Ca2+ store in skeletal muscle. J. Biol. Chem. 277, 5275-5284.

Visch, H., Rutter, G.A., Koopman, W.J.H., Varadi, A., Mitchell, K.J., van den Heuvel, L.P., Smeitink, J.A.M. and Willems, P.H.G.M. (2004) Inhibition of mitochondrial Na+-Ca2+ exchange restores stimulus-induced ATP production and Ca2+ handling in human complex I deficiency. J. Biol. Chem. 279, 40328-40336.

Boxma, B., de Graaf, R.M., van der Staay, G.W.M., van Alen, T.A., Ricard, G., Gabaldon, T., van Hoek, A.H.A.M., Moon-van der Staay, S.Y., Koopman, W.J.H., van Hellemond, J.J., Tielens, A.G.M., Friedrich, T., Veenhuis, M., Huynen, M., Hackstein, J.H.P. (2005) An anaerobic mitochondrion that produces hydrogen. Nature 434, 74-79.

Koopman W.J.H., Verkaart S, Visch H.J., van der Westhuizen F.H., Murphy, M.P., van den Heuvel L.W., Smeitink J.A., Willems P.H.G.M. (2005a) Inhibition of complex I of the electron transport chain causes oxygen radical-mediated mitochondrial outgrowth. Am. J. Physiol. Cell Physiol. 288, C1440-C1450.

Koopman, W.J.H., Visch H.J., Verkaart, S., van den Heuvel L.W., Smeitink J.A., Willems P.H.G.M. (2005b) Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency. Am. J. Physiol. Cell Physiol. 289, C881-C890.

Vogel, R., Dieteren, C.E.J., van den Heuvel, L.W.P.J., Willems, P.H.G.M., Koopman, W.J.H., Nijtmans, L.G.J. (2007a)  Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits. J. Biol. Chem. 282, 7582-7590.

Vogel, R., Janssen, J.R.J., van den Brand, M.A.M., Dieteren, C.E.J., Verkaart, S., Koopman, W.J.H., Willems, P.H.G.M., Pluk, W., van den Heuvel, L.W.P.J., Smeitink, J.A.M., Nijtmans, L.G.J. (2007b) Cytosolic signaling protein Ecsit also localizes to mitochondria where it associates with chaperone NDUFAF1 and functions in complex I assembly. Genes and Develop. 21, 615-624.

Koopman, W.J.H., Verkaart, S., Visch, H.J., van Emst-de Vries, S.E., Nijtmans, L.G.J., Smeitink, J.A.M., and Willems, P.H.G.M. (2007a) Human NADH: oxidoreductase deficiency: Radical changes in mitochondrial morphology? Am. J. Physiol. Cell Physiol. 293, C22-C29.

Koopman, W.J.H., Distelmaier, F., Hink, M.A., Verkaart, S., Wijers, M., Fransen, J., Smeitink, J.A.M., and Willems, P.H.G.M. (2008a) Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria. Am. J. Physiol. Cell Physiol. 294, C1124-C1132.

Koopman W.J.H., Sjoerd Verkaart,  Sjenet E. van Emst-de Vries, Sander Grefte, Jan A.M. Smeitink, Leo G.J. Nijtmans and Peter H.G.M. Willems. (2008b) Mitigation of NADH:ubiquinone oxidoreductase deficiency by chronic Trolox treatment. Biochim. Biophys. Acta. Bioenergetics 1777, 853-859.

Koopman W.J.H., Distelmaier, F., Esseling, J.J., Smeitink, J.A.M. and Willems, P.H.G.M. (2008c) Computer-assisted live cell analysis of mitochondrial membrane potential, morphology and calcium handling. Methods 46, 304-311.

Willems, P.H.G.M., Valsecchi, F., Distelmaier, F., Verkaart, S., Visch, H.J, Smeitink, J.A.M., and Koopman, W.J.H. (2008) Mitochondrial Ca2+ homeostasis in human NADH:ubiquinone oxidoreductase Cell Calcium 44, 123-133.

Eisenberg, I., Noversthern, N., Itzaki, Z., Becker-Cohen, M., Sadeh, M., Willems, P.H.G.M., Friedman, N., Koopman, W.J.H. and Mitrani-Rosenbaum, S. (2008) Mitochondrial processes are impaired in hereditary inclusion body myopathy. Hum. Mol. Genet. 17, 3663-3674.

Mortiboys, H., Thomas, K.J., Koopman, W.J.H., Klaffke, S., Sleiman, P., Olpin, S., Wood, N.W., Willems, P.H.G.M., Smeitink, J.A.M., Cookson, M.R. and Bandmann, O. (2008) Mitochondrial function and morphology are impaired in parkin mutant fibroblasts. Ann. Neurol. 64, 555-565.

Dieteren, C.E.J., Willems, P.H.G.M., Vogel, R.O., Swarts, H.G., Fransen, J., Roepman, R., Crienen, G., Smeitink, J.A.M., Nijtmans, L.G.J. and Koopman, W.J.H. (2008) Subunits of mitochondrial complex I exist as part of matrix- and membrane-associated subcomplexes in living cells. J. Biol. Chem. 283, 34753-34761.

Distelmaier, F., Visch, H.J., Smeitink, J.A.M., Mayatepek, E., Koopman, W.J.H. and Willems, P.H.G.M. (2009) The antioxidant Trolox restores mitochondrial membrane potential and Ca2+-stimulated ATP production in human complex I deficiency. J. Mol. Med. 87:515-522.

Distelmaier, F., Koopman, W.J.H., van den Heuvel, L.W., Rodenburg, R.J., Mayatepek, E., Willems, P.H.G.M. and Smeitink, J.A.M. (2009) Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain 132:833-842.

Willems, P.H.G.M., Smeitink, J.A.M. and Koopman, W.J.H. (2009) Mitochondrial dynamics in human NADH:oxidoreductase deficiency.  Int. J. Biochem. Cell Biol. 41:1773-1783.

Willems, P.H.G.M., Swarts, H.G., Hink, M.A. and Koopman, W.J.H. (2009) The use of fluorescence correlation spectroscopy to probe mitochondrial mobility and intra-matrix protein diffusion. Meth. Enzymol. 245:287-302.

Dieteren, C.E.J., Koopman, W.J.H. and Nijtmans, L.G.J. (2009) Tracing human mitochondrial complex I assembly by use of GFP-tagged subunits. Meth. Enzymol. 456:133-151.

Hoffmann, M., Bellance, N., Rossignol, R., Koopman, W.J.H., Willems, P.H.G.M., Mayatepek, E., Bossinger, O., Distelmaier, F. (2009) C. elegans ATAD-3 is essential for mitochondrial activity and development. PLoS ONE 4:E7644.

Valsecchi, F., Esseling, J.J., Koopman, W.J.H. and Willems, P.H.G.M. (2009) Calcium and ATP handling in NADH:ubiquinone oxidoreductase deficiency. Biochim. Biophys.  Acta Molecular Basis of Disease 1792:1130-1137.

Koopman, W.J.H., Nijtmans, L.G., Dieteren, C.E.J., Roestenberg, P., Valsecchi, F., Smeitink, J.A.M., Willems, P.H.G.M. (2009) Mammalian mitochondrial complex I: Biogenesis, Regulation and Reactive Oxygen Species generation. Antioxidants and redox signaling (in press).