Yeast has been successfully applied as model for aging and cell death research. Yeast cells undergo programmed cell death upon ageing, oxidative stress, starvation, radiation, unsuccessful mating, chemical warfare between yeast strains, mutation, and expression of pro-apoptotic mammalian proteins. Programmed cell death in yeast demonstrates typical features of apoptotic cell death known from metazoans, such as nuclear fragmentation, chromatin condensation, DNA fragmentation, phosphatidylserine externalization, and membrane blebbing. The underlying cellular mechanisms of apoptosis in yeast resemble mechanisms known from mammalian cells. The yeast caspase (YCA1) becomes activated and plays a pivotal role during many apoptotic scenarios in yeast, similar to caspases in mammalian cells. Highly comparable to mammalian apoptosis (e.g., during cell death in neurodegenerative disorders), mitochondria trigger cell death by producing reactive oxygen species (ROS), releasing protein factors, such as cytochrome c, yeast apoptosis-inducing factor (AIF1), and yeast endonuclease G (EndoG).
To date the most physiological form of apoptosis induction in yeast is aging. Chronological ageing, which constitutes a valuable model for the aging of non-mitotic mammalian cells, describes the time a yeast culture remains viable in stationary phase. In contrast replicative aging indicates the number of daughter cells an individual mother cell can produce. This form of aging has been successfully used as a model for dividing cells (stem cells).
The Basic Molecular Machinery of Yeast Apoptosis. Yeast shows a typical apoptotic phenotype including phosphatidylserine externalization, chromatin condensation, and DNA degradation. Accordingly, key players configuring the basic molecular machinery of cell death are conserved in yeast, among others the yeast caspase Yca1, the yeast homolog of mammalian HtrA2/OMI, NMA111, and the apoptosis-inducing factor Aif1. Furthermore, yeast programmed death can also be induced by both replicative and chronological aging and it has been linked to mitochondrial fragmentation, cytochrome c release, and cytoskeletal perturbations. The importance of histone modifications such as acetylation and phosphorylation in the regulation of celldeath execution is becoming evident. For instance, the histone deacetylases Hda1 and Rpd3 and the kinase Ste20 have been demonstrated to play a role in the regulation of yeast apoptosis. (D. Carmona-Guiterrez and F. Madeo, Mol. Cell, 2006)
Mechanisms of lipid-induced cell death
While cell death caused by lipids has dramatic effects on tissue homeostasis and organ function, its fundamental mechanism and regulation of lipotoxicity are mostly unknown. Increasing evidence suggests that the central mechanisms of lipotoxicity are conserved between mammals and yeasts. We use yeast as a simple and powerful model to quantify toxic effects of various lipid species, and to identify key regulators of lipotoxic pathways. Different lipid species like ceramides, free fatty acids (FA), diacylglycerol (DG) or cholesterol can lead to cell death. Signaling pathways involved in lipotoxicity may depend on different Protein Kinase C (PKC) isoforms or on Protein Kinase B (PKB). Cholesterol overload may trigger apoptosis via ER stress and activation of the unfolded protein response (UPR). This project focuses on the identification of branches of apoptosis activated in and crucial players necessary for lipid induced death.
Yeast as a model to study neurodegeneration
Neurotoxic proteins, such as mutant forms of á-synuclein, tau, prions, huntingtin, rhodopsin, and valosin-containing protein (Cdc48/VCP) are crucially involved in pathological neuronal degeneration during e.g. Parkinson disease, Alzheimer disease, prion diseases, Huntington disease. All these disorders are characterized by the accumulation of misfolded proteins that are proposed to be causative for neuronal cell death via poorly understood mechanisms. Yeast is an excellent model to analyze the consequences of the expression of neurotoxic proteins on cell viability and programmed cell death. Our previous work revealed that neurotoxic proteins can efficiently be expressed in yeast and result in increased susceptibility to undergo cell death. The long term goal is a further investigation of the molecular mechanisms behind toxicity, aggregation, and loss of physiological function of these neurotoxic proteins, using an easy-to-handle and genetically tractable yeast cell death model.
ContactAlterung & Zelltod - Labor Frank Madeo - Sekretariat