The interplay of Ca2+ homeostasis and vacuolar function in ageing and age-associated disease
We are interested in the many facets of cell death during physiological and pathophysiological ageing with focus on the interplay between calcium homeostasis, general vacuolar function and autophagy and its consequences for cellular survival. As Ca2+ regulates a diversity of generic processes such as cell proliferation, transcription, differentiation, or apoptosis, it is not surprising that cellular survival requires tightly controlled calcium fluxes. During non-pathological ageing, changes in calcium regulation are subtle and slowly progressing, leading to a mild increase in intracellular calcium levels in specific cell types. This might not lead to cellular demise per se but seems to render aged cells vulnerable to additional stress, for instance defects in autophagy, the major cellular bulk degradation process. Proteins involved in calcium signalling, transport and compartmentalization have been suggested to modulate autophagic processes in multiple ways. However, whether autophagy is stimulated or inhibited by calcium and calcium-handling proteins is a matter of debate, and underlying mechanistic links remain to be elucidated.
We are using the model organisms yeast (Saccharomyces cerevisiae) and fly (Drosophila melanogaster) to study the interplay between calcium homeostasis and autophagy as well as the physiological impact of these fundamental processes on cell death subroutines during ageing and in particular during age-associated human disease, with focus on neurodegeneration. Both model systems already provided substantial insights into evolutionary conserved ageing processes and the (mal)function of numerous disease-associated proteins, and our studies have uncovered molecular determinants of cellular demise linked to several neurotoxic proteins such as the Parkinson’s disease-associated protein α-synuclein.
Cell death; ageing; calcium homeostasis; autophagy; vacuolar function; neurodegeneration; yeast
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Büttner S, Faes L, Reichelt NR, Broeskamp F, Habernig L, Benke S, Kourtis N, Ruli D, D’hooge P, Ghillebert R, Eisenberg T, Carmona Gutierrez D, Franssens V, Harger A, Pieber TR, Freudenberger P, Kroemer G, Sigrist SJ, Winderickx J, Callewaert G, Tavernarakis N, Madeo F. The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson’s disease models. Cell Death Differ. 2012. 10:1038/cdd.2012.142
Büttner S, Ruli D, Vögtle FN, Galluzzi L, Moitzi B, Eisenberg T, Kepp O, Habernig L, Carmona-Gutierrez D, Rockenfeller P, Laun P, Breitenbach M, Khoury C, Fröhlich KU, Rechberger G, Meisinger C, Kroemer G, Madeo F. A yeast BH3-only protein mediates the mitochondrial pathway of apoptosis. EMBO J. 2011 Jun 14;30(14):2779-92.
October 22, 2015
Page editor: Elin Eriksson
Source: Department of Molecular Biosciences, The Wenner-Gren Institute