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Dysfunctional mitochondria as a neuronal pathogen

Projektbeschreibung

Mitochondriale RNA als Ursache für mitochondriale Erkrankungen

Mitochondrien sind eukaryotische Organellen, die den größten Teil der Energie für Zellen liefern. Die mitochondriale Dysfunktion beeinträchtigt den Zellstoffwechsel und löst mitochondriale Erkrankungen aus, die vor allem das energiehungrige Nervensystem zu betreffen scheinen. Das EU-finanzierte Projekt MitoTROJAN wird auf der Grundlage der Hypothese arbeiten, dass die mitochondriale doppelsträngige RNA (mtdsRNA) an der Neuropathologie von mitochondrialen Erkrankungen beteiligt ist. In einem multidisziplinären Ansatz anhand eines Mausmodells für mitochondriale Erkrankungen werden die Forschenden die Mechanismen der Immunantwort untersuchen, die mit der mtdsRNA assoziiert sind. Die Ergebnisse werden das bestehende Wissen über die Ätiologie von mitochondrialen Erkrankungen erweitern und neue therapeutische Ziele aufdecken, die sich möglicherweise zur Anwendung bei Neurodegeneration eignen.

Ziel

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 In addition, unpublished results of the host group showed that this neuronal population develop a robust cellular antiviral-like response elicited by mitochondrial double-stranded RNA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.

Koordinator

UNIVERSITAT AUTONOMA DE BARCELONA
Netto-EU-Beitrag
€ 172 932,48
Adresse
EDIF A CAMPUS DE LA UAB BELLATERRA CERDANYOLA V
08193 Cerdanyola Del Valles
Spanien

Auf der Karte ansehen

Region
Este Cataluña Barcelona
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 172 932,48