Interactions between mitochondria and the endoplasmic reticulum in cell physiology and disease
Mitochondria play a central role in a number of cell signalling pathways, including cell death and regulation of intracellular calcium homoeostasis. Mitochondria are highly dynamic organelles that can adapt their network in response to specific cellular needs. Indeed, they are able to constantly fuse and divide, and these events are intimately related to their metabolic functions and cellular stress signals. Impairment of mitochondrial physiology is linked to human diseases including neurodegenerative and metabolic disorders such as Parkinson’s disease and diabetes, and also in the progression of certain forms of cancer.
It has become clear recently that mitochondria do not function in isolation, but establish direct contact and communication with other cellular organelles to exchange metabolites and signals converging on, or streaming from, mitochondria. For instance, mitochondria are physically coupled to the endoplasmic reticulum through contact sites that act as a signalling platform. These are called mitochondria-associated membranes (MAM), and are essential for a number of processes, including intracellular calcium homoeostasis, lipid exchange, mitochondrial dynamics and motility, ROS production and apoptosis. Studies performed in the last decade have identified several proteins which directly tether the two organelles in MAMs and proteins enriched in these contact sites that play highly specialised homoeostatic or execution roles. However, the biogenesis, regulation and precise molecular mechanisms associated with these signalling platforms are still poorly understood.
Our current and future research programs focus on the understanding of the mechanisms regulating membranes dynamics and remodeling and how they converge to cellular functions and govern cell fate decisions. Using confocal and high-resolution live-cell microscopy, we study the intimate organelle synergy during the mitochondrial division process, where a 4-way contact between mitochondria, ER, lysosomes and Golgi-derived PI(4)P-containing vesicles occurs at fission sites. We aim to identify and functionally characterize new proteins regulating mitochondria-organelle contact sites, by coupling microscopy and proteomics to calcium and lipid fluxes analysis between the two organelles. We also investigate the relevance of mitochondrial dynamics and membrane contact sites to cell death and survival pathways, as well as cellular metabolism and to human diseases including cancer. Finally, we seek to elucidate how mitochondrial membranes remodeling leads to cytosolic mtDNA release and drives inflammation.