Characterization of the links between mitochondrial inner membrane homeostasis and interferon signaling – MIM-IR

Neuroinflammatory processes and mitochondrial dysfunction contribute to the pathogenesis of neurodegenerative diseases (e.g. Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Alzheimer, Huntington). However, the links between the two processes and the precise molecular mechanisms involved are still unclear. The mitochondrial inner membrane forms invaginations within the mitochondria, known as mitochondrial cristae. The organization of these cristae is essential for the mitochondrial function and the maintenance of mitochondrial DNA (mtDNA). Recently, disorganization of mitochondrial cristae structure has been linked to mtDNA release into the cytosol, and innate immune activation via the up-regulation of type I interferon (IFN).
In this project, 3 teams, each expert in their field (mitochondrial diseases, inflammation, neurodegenerative diseases) will join forces to determine the role of mitochondrial cristae disruption-driven mtDNA release in the neuroinflammation observed in neurodegeneration, through the study of 3 relevant primary mitochondrial disorders. Using different models of mitochondrial disease (cellular models (patient fibroblasts, iPSCs-derived-neurons, -astrocytes, -microglia) and mouse models) for which we have preliminary data in favor of a link between cristae disorganization and inflammation, we will (i) identify the molecular mechanisms involved in the loss of inner membrane integrity; (ii) characterize the IFN signaling and the mt-ISR; (iii) evaluate of the pathophysiological consequences of preventing cristae disruption or innate signaling.
Our project therefore aims to gain a better understanding of the link between mitochondrial defects, neuroinflammation and neuronal death, in order to develop effective new therapeutic approaches.