APOSITE aims to understand the molecular structure and dynamic mechanism of the BAX/BAK apoptotic foci, which mediate the permeabilization of the outer mitochondrial membrane during apoptosis. This cellular process constitutes the point-of-no-return in the cellular commitment to apoptosis, which plays a key role in essential biological processes like organ sculpture during embryo development, tissue homeostasis and the correct functioning of the immune system. In addition, dysregulation of apoptosis has been associated with diseases relevant for society, including cancer, stroke or neurodegenerative disorders.
To this aim, the project is divided into three main goals that will define the composition, assembly dynamics and structural organization of the supramolecular complexes underlying the apoptotic foci, as well as their functional relevance.
APOSITE has advanced our understanding of the mechanisms that mediate mitochondrial permeabilization during apoptosis. We found that BAX and BAK present distinct assembly properties, so that their balance determines the growth rate of the apoptotic pore and with it, the downstream consequences for inflammatory signaling. We have also dissected the protein and lipid composition in the environment of the apoptotic pores formed by BAX and BAK, and defined their role in mitochondrial permeabilization. We discovered that both proteins outside the BCL-2 family, as well as lipids, can modulate the growth of the apoptotic pore and its inflammatory function. We have developed a new microscopy method that correlates the copy number of individual apoptotic pores with their nanoscale organization and the underlying mitochondrial ultrastructure. Thanks to this, we could visualize that the BAX and BAK assemblies localize to disruptions at the mitochondrial outer membrane. Our data suggest that it is the membrane shape that defines the shape of the BAX and BAK structures and that the outer and inner membrane cooperate to drive the growth of the apoptotic pore.
