Targeting brain mitochondrial bioenergetics as an attractive therapeutic avenue for Rett syndrome: evidence from female mouse models

Mitochondrial metabolism plays a crucial role in the regulation of brain function and behaviour. Many studies point towards a critical involvement of alterations in brain mitochondrial bioenergetics in the pathogenesis of a broad variety of conditions, including early-onset neurological diseases such as Rett syndrome (RTT), a rare genetic disorder. RTT patients are mainly females and manifest cognitive and motor impairments paired with physiological complications, since infancy. Defective brain mitochondrial energy metabolism, quality control and antioxidant defense have been identified in RTT patients and mouse models. The present thesis aimed to verify whether the rescue of brain mitochondrial bioenergetic alterations counteracts the neuropathological phenotype of RTT female mouse models. Three compounds, the anti-diabetic drug Metformin, the RhoGTPase activator CNF1 and the cannabinoid receptor 1 inhibitor Rimonabant, were selected for their recognized capability to modulate brain mitochondrial respiratory chain complex activity and their effects on the neuropathological phenotype of fully symptomatic RTT mice were addressed as an efficacy index. As expected, all the compounds restored mitochondrial dysfunctions in RTT mouse brain. In all three studies, such a restoration was accompanied by a selective improvement of cognitive abilities, while beneficial effects on RTT-related phenotypical alterations were not observed. Present findings corroborate an intimate connection between mitochondrial health and cognition in RTT context. The molecular investigation of mechanisms underlying the effects of the treatments suggests that restoration of the mitochondrial quality control may explain the beneficial outcomes of all the molecules tested on the defective brain mitochondria bioenergetics, highlighting a promising therapeutic target to treat RTT. Future studies will have to clarify whether targeting mitochondria during early life could provide better therapeutic efficacy for RTT. The generalization of our findings to other RTT-like diseases should be also addressed, in order to open up novel therapeutic opportunities for a wide range of conditions.