MIM pores: composition, structure and function

Mitochondria are double-membrane organelles involved in key biological processes such as metabolism, calcium homeostasis and cell death. A major role of mitochondria in inflammation, a mechanism of innate immunity against tissue damage, has been recently recognized. Due to their proteobacterial origin, certain mitochondrial matrix contents can act as potent immune agonists when exposed to the cytosol. Hence, knowing the dynamics and molecular architecture of the mitochondrial pores mediating the release of these mitochondrial contents is crucial for understanding the role of mitochondria in inflammation.While in apoptosis BAX and BAK proteins form pores at the mitochondrial outer membrane (MOM), the components and mechanisms that regulate the permeabilization of the mitochondrial inner membrane (MIM) remain unknown. MITOPORE aims to unravel the identity, dynamic architecture and regulation of the pores that permeabilize the MIM and to understand how they control mitochondria-driven inflammation. We will reach this goal by building on our expertise in membrane biology and advanced imaging to:1)Identify the mediators and regulators as well as the physical forces controlling MIM pores with complexome profiling and image-based biophysical analysis.2)Define their contribution to anti-mitochondria immunogenicity through activation of intracellular immune receptors and communication with the tissue microenvironment in cellular and in vivo models.3)Determine the assembly dynamics and molecular structure of MIM pores and their regulators by combining single particle and super-resolution imaging and advanced electron microscopies. MITOPORE is expected to provide textbook knowledge about the mitochondrial contribution to inflammation. The established workflows will open new avenues for membrane and organelle biology research. Ultimately, understanding the structure/function of MIM pores holds promise to guide the development of modulators against inflammatory diseases.