Peroxisome dynamics
Dr E Hettema |
Career History2008 - present: Wellcome Trust Senior Research Fellow in Basic Biomedical Science at University of Sheffield |
| My group aims to improve understanding of the molecular mechanisms underlying peroxisome dynamics at the cellular level. |
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Cells contain a large number of distinct membrane bound organelles. These compartments rely on complex machineries to acquire and maintain their unique composition and function. We are studying one of these organelles, the peroxisome. Lack of functional peroxisomes results in a deficiency of a large number of enzymatic reactions and a disorder called Zellweger (ZS-) or cerebro-hepato-renal syndrome. Proteins required for peroxisome formation are called peroxins and these have been found mutated in ZS patients. |
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| Peroxisomes multiply by growth and division. The endoplasmic reticulum (ER) provides peroxisomes with membrane constituents allowing these organelles to grow, after which the organelles divide and distribute between mother and daughter cell. The number of peroxisomes per cell is influenced by intracellular and extracellular factors and these can induce proliferation or breakdown. How these processes are regulated and integrated into cellular metabolism is poorly understood. |
 Schematic representation of peroxisome dynamics in the yeast Saccharomyces cerevisiae.A) Peroxisomes multiply and are subsequently transported to the newly forming daughter cell via an actin-myosin-based process. Approximately half the number of the peroxisomes are anchored to the periphery of mother cells and remain there. These opposing processes ensure peroxisome segregation with high fidelity. B) Peroxisomes can be induced to proliferate under conditions of high requirement for these organelles. A subsequent shift to conditions where peroxisomes are superfluous induces their rapid breakdown by autophagy. Selective breakdown of peroxisomes is named pexophagy. |
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Genetic model organisms to study peroxisome dynamics and functioning |
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Fluorescence micrograph of Control and mutant S. cerevisiae cells and D. melanogaster S2 cells expressing a peroxisomal GFP marker. Mutants in S.cerevisiae cells are gene deletion mutants. Mutant phenotypes in D. melanogaster S2 cells were created by temporary inactivation of genes with RNAi. Blue circumference of yeast cells is artificially coloured bright field image. Nuclei are stained with DAPI in S2 cells and artificially coloured blue in images. |
| More recently we have extended our studies into other model organisms including the fruit fly Drosophila melanogaster, the slime mould Dictyostelium discoideum and human cells. For instance, a genome-wide RNAi screen in Drosophila cells identified many of the known proteins involved in peroxisome formation and peroxisome multiplication. Interestingly, we also identified several new genes that appear to be involved in formation and regulation of peroxisome dynamics. We use molecular cell biological approaches including live-cell imaging, genome-wide RNAi screens, yeast genetics, proteomics and protein-protein interaction studies to characterise the function of these new proteins. Although our main interest is in a fundamental understanding of peroxisome dynamics and its role in peroxisome functioning, we are also following up on lines of research that potentially have medical implications. |
Selected Publications |
| Atg36: The Saccharomyces cerevisiae receptor for pexophagy Motley, A.M., Nuttall, J.M. and Hettema, E.H. Autophagy (2012) 8, p1680-1681 |
| Pex3-anchored Atg36 tags peroxisomes for degradation in Saccharomyces cerevisiae. Motley, A.M., Nuttall, J.M. and Hettema, E.H. EMBO J. (2012) 31 p2852-68 |
| Farnesyl diphosphate synthase, the target for nitrogen-containing bisphosphonate drugs, is a peroxisomal enzyme in the model system Dictyostelium discoideum Nuttall, J.M., Hettema, E.H. and Watts, D.J Biochem. J (2012) 447 p353-361 |
| Peroxisome biogenesis: recent advances Nuttall, J.M., Motley, A.M. and Hettema, E.H. Curr. Opin. Cell Biol. (2011) 23, p421-426 |
| A dual function for Pex3p in peroxisome formation and inheritance Munck, J.M., Motley, A.M., Nuttall, J.M. and Hettema, E.H. J. Cell Biol. (2009) 187, p463 - 71. |
| How peroxisomes multiply Hettema, E.H. and Motley, A.M. J. Cell Sci. (2009) 122, p2331 - 2336 |
| Dnm1-dependent peroxisome fission requires Caf4, Mdv1 and Fis1. Motley, A.M., Ward, G.P., and Hettema, E.H. J. Cell Sci. (2008) 121 p1633 - 1640 |
| Yeast peroxisomes multiply by growth and division Motley, A.M. and Hettema, E.H. J. Cell Biol. (2007) 178, p399 - 410 |
Immunofluorescence micrograph of human fibroblasts stained for the peroxisomal enzyme catalase in control and pex-deficient cells.