Interrogating the link between mitochondrial dysfunction and type I interferon signalling – MITIgATe
Mitochondria act as critical metabolic hubs and signalling platforms, and understanding the potential of mitochondrial DNA and RNA to act as immune-modulators in the context of homeostasis and disease is an area of intense scientific focus. Notably, there is increasing recognition that aberrant engagement of the innate immune system by mitochondrial nucleic acid, upon mitochondrial dysfunction, can contribute to the pathology of a broad range of diseases, including autoimmunity and neuroinflammation. However, the mechanisms of mitochondrial nucleic acid release into the cytosol are poorly understood.
Very recently, we showed that mutations in ATAD3A, encoding the mitochondrial ATPase family AAA domain-containing protein 3A, with no known immune function, cause mitochondrial DNA-dependent up-regulation of type I interferon signalling in the context of autoimmune and neurological pathology. In conjunction with findings of enhanced interferon signalling in another mitochondrial disease, our work raises the possibility of a broader association between mitochondrial disorders and abnormal interferon induction, with pathogenic potential.
Based on my combined expertise in innate immunity and mitochondrial biology, I will study this Mendelian disease as an opportunity to dissect out the physiological roles of ATAD3A and better understand the link between mitochondrial integrity and immune signalling. Moreover, using agnostic strategies in vitro and in a clinical setting, I propose to interrogate the association between mitochondrial dysfunction and IFN signalling to shed more light on the processes maintaining mitochondrial compartmentalisation and immune homeostasis, to generate future research and therapeutic leads.
Madame Alice LEPELLEY (Imagine -Institut des maladies génétiques)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IMAGINE Imagine -Institut des maladies génétiques
Help of the ANR 346,929 euros
Beginning and duration of the scientific project: September 2022 - 36 Months