Mitochondrial dynamics in (patho)hysiology

 

Normal cell functioning and survival requires energy in the form of ATP that is generated by a variety of metabolic pathways. Within this metabolism, the mitochondrial oxidative phosphorylation (OXPHOS) system is among the prime producers of ATP. Proper OXPHOS function is also required to sustain many other mitochondrial processes including the exchange of ions and metabolites with the cytosol. In this sense, the OXPHOS system plays a key role in various cellular processes like adaptive thermogenesis, innate immune responses, calcium and redox signalling, and programmed cell death (apoptosis). 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.

My group focuses on gaining a quantitative mechanistic understanding of mitochondrial (patho)physiology at the (sub)cellular level during mitochondrial dysfunction. More specifically, we aim to understand the relationship between mitochondrial (dys)function, mitochondrial (ultra)structure, reactive oxygen species (ROS)-induced signaling and/or stress, and adaptive cell survival responses. When appropriate, the obtained fundamental insights are valorized in collaboration with Khondrion BV, which focuses on the rational design of novel therapeutics for mitochondrial disease. Since mitochondrial metabolism is intricately interfaced with its cellular environment, research is performed using various (patient- and animal-derived) cell models. In this sense, we have specialized in combining biochemical and molecular cloning strategies with fluorescent reporter analysis, state-of-the-art quantitative life-cell/single-molecule microscopy and spectroscopy, image processing and quantification, mathematical modeling, high-resolution respirometry and machine learning techniques. This unconventional combination of expertise bridges the gaps between researchers from different backgrounds (medical doctors, biologists, biochemists, biophysicists, and mathematicians).

Recent publications

  1. Multiplexed high-content analysis of mitochondrial morphofunction using live-cell microscopy.Iannetti, E.F., Smeitink, J.A.M., Beyrath, J., Willems, P.H.G.M., Koopman, W.J.H. Nature Protoc. 11:1693-1710.

  2. Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth. Schöckel L, Glasauer A, Basit F, Bitschar K, Truong H, Erdmann G, Algire C, Hägebarth A, Willems PH, Kopitz C, Koopman WJ, Héroult M. Cancer Metab. 2015 Oct 20;3:11.

  3. Complex I and complex III inhibition specifically increase cytosolic hydrogen peroxide levels without inducing oxidative stress in HEK293 cells. Forkink M, Basit F, Teixeira J,Swarts HG, Koopman WJ, Willems PH.  Redox Biol. 2015 Oct 23;6:607-616.

  4. Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia. Manjeri GR, Rodenburg RJ, Blanchet L, Roelofs S, Nijtmans LG, Smeitink JA, Driessen JJ, Koopman WJ, Willems PH. J Inherit Metab Dis. 2015 Aug 27.

  5. Redox Homeostasis and Mitochondrial Dynamics. Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ. Cell Metab. 2015 Aug 4;22(2):207-18. doi: 10.1016/j.cmet.2015.06.006.

  6. Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Liemburg-Apers DC, Willems PH, Koopman WJ, Grefte S. Arch Toxicol. 2015 Jun 6. [Epub ahead of print]

  7. Skeletal muscle mitochondria of NDUFS4(-/-) mice display normal maximal pyruvate oxidation and ATP production. Alam MT, Manjeri GR, Rodenburg RJ, Smeitink JA, Notebaart RA, Huynen M, Willems PH, Koopman WJ. Biochim Biophys Acta. 2015 Feb 14. pii: S0005-2728(15)00031-6.

  8. Toward high-content screening of mitochondrial morphology and membrane potential in living cells. Iannetti EF, Willems P, Pellegrini M, Beyrath J, Smeitink J, Blanchet L, Koopman WJ. Int J Biochem Cell Biol. 2015 Feb 8. pii:S1357-2725(15)00030-8.

  9. Live-cell assessment of mitochondrial reactive oxygen species using dihydroethidine. Forkink M, Willems PH, Koopman WJ, Grefte S. Methods Mol Biol. 2015;1264:161-9

  10. Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning. Blanchet L, Smeitink JA, van Emst-de Vries SE, Vogels C, Pellegrini M, Jonckheere AI, Rodenburg RJ, Buydens LM, Beyrath J, Willems PH, Koopman WJ. Sci Rep. 2015 Jan 26;5:8035.

  11. Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Distelmaier F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, Heil S, Keijer J, Fransen J, Imamura H, Danhauser K, Seibt A, Viollet B, Gellerich FN, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ. Biochim Biophys Acta. 2015 Mar;1852(3):529-40.

  12. Mitochondrial hyperpolarization during chronic complex I inhibition is sustained by low activity of complex II, III, IV and V. Forkink M, Manjeri GR, Liemburg-Apers DC, Nibbeling E, Blanchard M, Wojtala A, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ. Biochim Biophys Acta. 2014 Aug;1837(8):1247-56.

  13. OXPHOS mutations and neurodegeneration. Koopman WJ, Distelmaier F, Smeitink JA, Willems PH. EMBO J. 2013 Jan 9;32(1):9-29.

  14. BOLA1 is an aerobic protein that prevents mitochondrial morphology changes induced by glutathione depletion. Willems P, Wanschers BF, Esseling J, Szklarczyk R, Kudla U, Duarte I, Forkink M, Nooteboom M, Swarts H, Gloerich J, Nijtmans L, Koopman W, Huynen MA. Antioxid Redox Signal. 2013 Jan 10;18(2):129-38.

  15. Trolox-sensitive reactive oxygen species regulate mitochondrial morphology, oxidative phosphorylation and cytosolic calcium handling in healthy cells. Distelmaier F, Valsecchi F, Forkink M, van Emst-de Vries S, Swarts HG, Rodenburg RJ, Verwiel ET, Smeitink JA, Willems PH, Koopman WJ. Antioxid Redox Signal. 2012 Dec 15;17(12):1657-69.

  16. Monogenic mitochondrial disorders. Koopman WJ, Willems PH, Smeitink JA. N Engl J Med. 2012 Mar 22;366(12):1132-41.

  17. Solute diffusion is hindered in the mitochondrial matrix. Dieteren CE, Gielen SC, Nijtmans LG, Smeitink JA, Swarts HG, Brock R, Willems PH, Koopman WJ. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8657-62.