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The Department of Biomedicine

BBB Seminar: Werner J. H. Koopman

Cellular pathophysiology and therapy of mitochondrial OXPHOS disorders

Werner J. H. Koopman
Department of Biochemistry, Nijmegen Centre  for Molecular Life Sciences (NCMLS), Radboud University Medical Centre, Nijmegen, The Netherlands

To function normally, human cells require energy in the form of ATP that is generated by a variety of metabolic pathways. In most cell types ATP is primarily produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. The latter consists of 5 multi-subunit complexes (complex I to complex V) 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. Importantly, mitochondria do not only generate ATP but also play key roles in other important cellular processes, such as adaptive thermogenesis, ion homeostasis, innate immune responses, production of reactive oxygen species (ROS), and programmed cell death (apoptosis).

Mitochondrial dysfunction is not only associated with relatively rare monogenic mitochondrial disorders but is also observed during more common pathologic conditions, such as Alzheimer’s disease, Parkinson’s disease, cancer, cardiac disease, diabetes, epilepsy, Huntington’s disease, and obesity. In addition, mitochondrial function is inhibited by environmental toxins and frequently used drugs. Also during normal human aging, a progressive decline in the expression of mitochondrial genes is observed. Mutations in OXPHOS structural genes are associated with neurodegenerative diseases including Leigh Syndrome, which is probably the most classical OXPHOS disease during early childhood. During the last decade analysis of cells from patients with monogenic mitochondrial diseases has considerably advanced our general understanding of the cellular (patho)physiology of mitochondrial (dys)function. How these insights were obtained and how they can contribute to the rational design of intervention strategies for mitochondrial dysfunction will be summarized. To this end, our on-going research on human mitochondrial OXPHOS deficiency will be presented as an example of mitochondrial medicine.


Host: Karl Johan Tronstad , Department of Biomedicine


Key references:

1. Koopman, W.J.H., Distelmaier, F., Smeitink, J.A.M., Willems, P.H.G.M. (2012) OXPHOS mutations and neurodegeneration. EMBO J. (in press).

2. Distelmaier, F., Valsecchi, F., Forkink, M., van Emst-de Vries, S., Swarts, H., Rodenburg, R.J., Verwiel, E., Smeitink, J.A.M., Willems, P.H.G.M., Koopman, W.J.H. (2012) Trolox-sensitive ROS regulate mitochondrial morphology, oxidative phosphorylation and cytosolic calcium handling in healthy cells. Antioxid. Red. Signal. (in press).

3. Willems, P.H.G.M., Wanschers, B., Esseling, J., Szklarzyk, R., Kudla, U., Duarte I., Nooteboom, M., Forkink, M., Swarts, H., Gloerich, J., Nijtmans, L.J., Koopman, W.J.H., Huynen, M. (2012) BOLA1 is an aerobic protein that prevents mitochondrial morphology changes induced by glutathione depletion. Antioxid. Red. Signal. 17:1657-1669.

4. Koopman, W.J.H., Willems, P.H.G.M., Smeitink, J.A.M. (2012) Monogenic mitochondrial disorders. N. Engl. J. Med. 366:1132-1141.

5. Dieteren, C.E.J., Gielen, S.C.A.M., Nijtmans, L.G., Smeitink, J.A.M., Swarts H., Brock, R., Willems, P.H.G.M., Koopman, W.J.H. (2011) Solute diffusion is hindered in the mitochondrial matrix. Proc. Natl. Acad. Sci. USA 108:8657-8662.

6. Koopman, W.J.H., Nijtmans, L.G., Dieteren, C.E.J., Roestenberg, P., Valsecchi, F., Smeitink, J.A.M., Willems, P.H.G.M. (2010) Mammalian mitochondrial complex I: Biogenesis, regulation and reactive oxygen species generation. Antioxid. Red. Signal. 12:1431-1470.

7. 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.