Cell Death Regulation

Programme Leader: Dr L. Miguel Martins

We are currently recruiting post-doctoral scientists, for more information contact Dr. Martins

Summary of Research Interests

The focus of our research is to better understand the control of cellular death processes in normal cells as well as in pathological states where alterations of these processes have occurred. Our aim is to achieve a better understanding of the regulatory mechanisms controlling cell death. Understanding the basic biology of these processes can provide insights that might lead to targeted treatment solutions that will act on pathways and alter disease at its cause resulting in a better type of medicine.

1. HtrA2 and PINK1 and their role in stress response.

Part of our current research addresses the function of mitochondrial proteins HtrA2 and PINK1 and their role in stress responses. Mutations in HtrA2 and PINK1 have been linked to Parkinson’s disease. We have recently identified a mitochondrial stress-sensing pathway that involves the interaction between these two proteins.

Figure 2

Currently our work on this stress-sensing pathway focuses on the changes in gene expression in cells subjected to enhanced mitochondrial stress (figure 3).

Figure 3 Using genetic, biochemical and bioinformatics techniques we have identified a transcriptional program that is activated following mitochondrial stress and that might contribute to the aetiology of neurodegenerative diseases like Parkinson’s disease.

2. Regulators of mitochondrial-dependent cell death.

We are also interested in identifying novel regulators of mitochondrial-dependent cell death using functional genomics screens. Towards this goal, we are using both RNA interference (RNAi) and enhancer trap technology to identify modulators of this process.

As an example, we have recently conducted an RNAi screen to identify modulators of apoptosis induced by ultraviolet light (outlined in Figure 4). By comparing the population of RNAi constructs present in cultured human cells both before and after induction of apoptosis with UV, we were able to identify RNAi molecules selectively enriched in cells surviving this death stimulus. We are currently characterizing genes selectively targeted by these RNAi constructs with the objective of understanding how these genes control cell death.

Figure 4 Outline of a recently conducted RNAi screen to identify modulators of apoptosis induced by ultraviolet light.

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Recent Research Publications:

de Castro, I. et al. Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster. Cell Death and Differentiation (2012), Pubmed

Gerhardt, E. et al. Idebenone and Resveratrol Extend Lifespan and Improve Motor Function of HtrA2 Knockout Mice. PLoS One, (2011) Pubmed

Fitzgerald, J.C. et al. Phosphorylation of HtrA2 by Cyclin Dependant Kinase 5 modulates its neuroprotective function. Cell Death and Differentiation, (2011) PubMed

Deas, E. et al. PINK1 Cleavage at position 103 by the mitochondrial protease PARL. Human Molecular Genetics, (2010) PubMed

Lam, D. et al. Drosophila happyhour modulates JNK-dependent apoptosis. Cell Death and Disease, (2010) PubMed

Kieper et al., Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1. Experimental Cell Research, (2010) PubMed

David Lam and L. Miguel Martins. MAP4K3 enhances the expression of the BH3-only protein BID, Cell Cycle (2009) PubMed

Lam, D. et al. MAP4K3 modulates cell death via the post-transcriptional regulation of BH3-only proteins, PNAS (2009) PubMed

Tain, L.S. et al. Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin, Cell Death and Differentiation (2009) PubMed

Moisoi, N, et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of brain-specific transcriptional stress response, Cell Death and Differentiation (2009) PubMed

Kawamoto, Y. et al. Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with α-synucleinopathies. Journal of Neuropathology and Experimental Neurology (2008) PubMed

Plun-Favreau, H. et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol (2007) PubMed

Review Articles:

Iaccarino, I., Martins, L.M. Therapeutic Targets in Cancer Cell Metabolism and Death. Cell Death and Differentiation (2011) PubMed

Plun-Favreau, H., Lewis, P., Hardy, J., Martins, L. M., Wood, N. Cancer and Neurodegeneration: Between the Devil and the Deep Blue Sea. PloS Genetics (2010) PubMed

de Castro, I., Martins, L.M. Loh, S. H. Y. Mitochondrial Quality Control and Parkinson’s Disease: A Pathway Unfolds. Molecular Neurobiology (2010) PubMed.

de Castro IP, Martins, LM, Tufi R Mitochondrial quality control and neurological disease: an emerging connection. Expert Rev. Mol. Med. (2010) PubMed