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Molecular Anatomy and Pathophysiology of the endoplasmic reticulum-mitochondria interface

Final Report Summary - ERMITO (Molecular Anatomy and Pathophysiology of the endoplasmic reticulum-mitochondria interface)

Organelles, the constituents of every cell in our body, are not randomly positioned. They interact by some poorly characterized mechanisms. The interaction between mitochondria, the powerhouses of the cell, and the endoplasmic reticulum, the factory where all the proteins are produced, is particularly important; yet, how they engage in such interactions is unclear. The purpose of this grant was to shed light on the components of this machinery and on how this interaction is important for the life of the cell.

During the tenure of this grant we explored the function of this interface in several models of development and disease. First, we investigated the consequence of the loss of the master regulator of this juxtaposition, a mitochondrial protein called Mfn2, on heart biology. To properly beat, the heart needs that mitochondria and endoplasmic reticulum are placed at the right distance. We however discovered an unexpected role for this protein not in the mature, adult heart, but during its development: precursor cells of the cardiomyocytes (the cells that constitute the heart) require Mfn2 to properly differentiate and become functional, beating cardiomyocytes. Indeed, lack of Mfn2 interrupts a crucial signal that tells to the heart stem cells to become a heart cell, skewing their differentiation towards fibroblasts, the cells that in our body are responsible for the production of collagen (the scaffold of all our tissues). This discovery indicates that the interface endoplasmic reticulum-mitochondria has a previously unappreciated role also in differentiation (Kasahara et al., Science 2013). We also explored the role of this protein Mfn2 in the fruitfly, a useful model organism to identify pathways altered following inactivation of genes. We discovered that when endoplasmic reticulum and mitochondria are distant, the latter becomes very dysfunctional, triggering the so called “ER stress response”, a complex genetic program that informs the cell about the distress of the endoplasmic reticulum. Unexpectedly, correction of this ER stress response also corrects the fruitflies living without the Mfn gene, offering a potential therapeutic strategy for patients with Charcot-Marie-Tooth type IIa, characterized by mutations in Mfn2 (Debattisti et al., J. Cell Biol. 2014). We extended the study of the role of the ER stress response in detecting mitochondrial problems and we recently discovered that this response is crucial to detect aging mitochondria in the skeletal muscle, and to hence send a signal to the whole body, by causing the production of the hormone FGF21. This increase in muscle derived FGF21 causes the senescence of distant organs, including skin, liver and gut. Hence, the ER-mitochondria intercommunication not only controls development, but also senescence (Tezze, Romanello et al., Cell Metabolism 2017).

In more molecular experiments, we are now providing a catalogue of the proteins that keep these two organelles close, or separated. These catalogues not only will serve as a resource for the community of researchers, but will also open completely new avenues of research in several diseases. Indeed, among the unexpected genes important for the ER-mitochondria proximity, we found genes involved in respiratory diseases, in genetic muscular diseases, in diabetes and in neurodegenerative disorders. These catalogues will therefore represent a cornerstone to include studies on this interface in several disease-related conditions.

In summary, this project allowed us to shed light at an unprecedented level on how two different cellular components interact, and on what are the consequences of this interaction.