MOLECULAR AND PHENOTYPICAL CHARACTERIZATION OF MICE DEFICIENT IN ASTROCYTIC MITOCHONDRIAL COMPLEX I

We have previously shown that a key player in the astrocyte-neuron metabolic cooperation and mouse behavior lies in the ability of astrocytes to physiologically generate reactive oxygen species (ROS) by mitochondrial complex I (CI). However, direct and unambiguous demonstration that the function of astrocytic CI on sustaining cognition is due to its ability to modulate intercellular signaling through ROS is lacking. To address this issue, we generated mice deficient in Ndufs2, a CI subunit that is essential for the assembly and stability of its Q-module and catalytic function, in astrocytes. Ndufs2-lox/lox male and female mice at the age of 3 months were intravenously injected with PhP.eB-serotype adenoviruses (AAV) expressing Cre recombinase governed by the short GAFP promoter (gfa-ABC1D). We found that astrocytic-specific Ndufs2-KO mice displayed a marked arrest in weight gain one month after AAV administration, which was severely and suddenly aggravated at month three, preceding immediate death. Behavioral characterization of these mice two months after AAV administration showed cognitive and motor alterations but not signs of pain or suffering. Bioenergetic analysis of immunomagnetically isolated astrocytes in fresh, using the Seahorse technology, showed a decline in basal and maximal respiration, as well as in the spare respiratory capacity. These preliminary results indicate that the mitochondrial complex I in astrocytes is essential for life. Ongoing molecular analysis of these mice will clarify which function(s) of mitochondrial complex I in astrocytes mediate the severe phenotype observed.