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Projects. Life and Earth Sciences

AGC1 deficiency and calcium signaling in mitochondria: a new disease model for the study of pathogenic mechanisms and for the development of therapeutic strategies.

Lead Researcher: Jorgina Satrústegui Gil-Delgado
Research Centre: Centro de Biología Molecular Severo Ochoa. CSIC-UAM. Madrid.

Abstract: 

Jorgina Satrústegui Gil-DelgadoCa2+ activation of mitochondrial respiration in neurons is extremely sensitive to malate-aspartate shuttle (MAS) activity, which is controlled by the MAS component, mitochondrial aspartate-glutamate carrier Aralar/AGC1/Slc25a12, a Ca2+ regulated transporter. This challenges the long lasting view that the Ca2+ uniporter controls respiration and suggests that alternative mechanisms regulate respiration in brain cells which will be studied in the present project. In the context of rare diseases, the AGC1 KO mouse recapitulates many aspects of AGC1 deficiency, a rare human disease causing severe hypotonia, arrested psychomotor development, hypomyelination and epilepsy. The project aims at using neurons from AGC1 KO to test alternative substrates on neuronal respiration, including ketone bodies. These studies may be used to implement therapeutic strategies in epilepsies of unknown origin and resistant to pharmaceuticals such as the ketogenic diet. In AGC1 deficiency, the lack of MAS in neurons emerges as the pathogenic mechanism of the disease, and the lack of this NADH shuttle as the main reason whereby brain aspartate and N-acetylaspartate levels drop dramatically in patients and mice. However, whether MAS activity itself or its Ca2+ regulation properties are actually involved in the pathogenesis of the disease is still unknown. This will be addressed by developing a mouse with mutations in the Ca2+ binding motifs of AGC1 which have been shown to abolish Ca2+ regulation while maintaining the transporter activity. This will allow to study the precise role of Ca2+-binding in MAS function and neuronal respiration in response to different stimuli.


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