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Dysfunctional mitochondria as a neuronal pathogen

Project description

Mitochondrial RNA as the culprit of mitochondrial disease

Mitochondria are eukaryotic organelles that generate most of the cell’s energy. Mitochondrial dysfunction affects cellular metabolism and leads to mitochondrial disease (MD) that seems to particularly affect the high-energy requiring nervous system. The EU-funded MitoTROJAN project will work under the hypothesis that mitochondrial double-stranded RNA (mtdsRNA) is implicated in MD neuropathology. Researchers will undertake a multi-disciplinary approach, and using a mouse MD model, they will study the immune response mechanisms associated with mtdsRNA. Results will expand current knowledge on the aetiology of MD and identify novel therapeutic targets with potential application in neurodegeneration.


The symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity. Due to its archeobacterial origin, mitochondria has been posited as a potential source of molecules that can elicit cellular responses to pathogens. Among other key functions, mitochondria generates most of the energy required by cells. Alterations in components of the mitochondrial energy-generating machinery lead to primary mitochondrial disease (MD), a group of highly invalidating human conditions with no effective treatment. High-energy-requiring cells, such as neurons, are especially affected in MD. However, not all neuronal populations are equally affected and the molecular determinants of this susceptibility are currently unknown. Recently, Quintana´s lab uncovered that GABAergic neurons in the Globus Pallidus (GPe) of a mouse model of Leigh syndrome (LS) are particularly sensitive to MD leading to fatal encephalopathy, recapitulating the human pathology. In addition, unpublished results of the host group showed that this neuronal population develop a robust cellular antiviral-like response elicited by mitochondrial double-stranded RNA (mtdsRNA). Nevertheless, the contribution of mtdsRNA release in the MD progression has never been defined. Thus, the main goal of MitoTROJAN is to identify the effect of mtdsRNA-induced neuropathology in the context of mitochondrial dysfunction with the overarching goal of providing novel targets for the treatment of MD. By combining mouse genetics with cutting-edge molecular biology and multi-omics approach, I will carry out a multidisciplinary strategy to i) parse the molecular mechanisms of mtdsRNA-induced neuropathology and ii) characterise the antiviral response-induced protein shutdown in affected neurons. Overall results will provide new insight on an uncharacterized mechanism of mitochondria-mediated neurodegeneration and will help to identify novel therapeutic targets for MD and other neurodegenerative diseases.


Net EU contribution
€ 172 932,48
08193 Cerdanyola Del Valles

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Este Cataluña Barcelona
Activity type
Higher or Secondary Education Establishments
Total cost
€ 172 932,48