Dysfunctional mitochondria as a neuronal pathogen

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 In addition, unpublished results of the host group showed that this neuronal population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 mtdsRNAinduced
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.