Descrizione del progetto
Approfondimenti meccanicistici sull’espressione genica mitocondriale
Oltre al DNA nucleare, le cellule eucariotiche contengono il DNA mitocondriale, che codifica le sottounità degli enzimi della catena di trasporto degli elettroni. Sebbene ciò sia un’indicazione chiara dell’importanza dell’espressione genica mitocondriale per il metabolismo cellulare, sono disponibili poche informazioni meccanicistiche su come essa viene raggiunta e regolata. È risaputo che la traduzione genica mitocondriale sia regolata tramite l’azione di fattori codificati dal nucleo. Il progetto MiXpress, finanziato dal Consiglio europeo della ricerca, propone di esaminare le diverse fasi del processo dell’espressione genica mitocondriale. Verrà posto l’accento sulla cooperazione con i componenti codificati dal nucleo per comprendere la modalità di risposta delle cellule al fabbisogno energetico.
Obiettivo
Mitochondrial gene expression is essential for cellular metabolism and energy supply since 13 core subunits of the OXPHOS system are encoded on the mitochondrial genome. Despite its importance for cellular function, mitochondrial gene expression (mitoGE) and its regulation are not understood at a mechanistic level. To this end, we demonstrated that mitochondrial translation is prone to regulation, responding to influx of nuclear-encoded proteins . However, the mechanisms that regulate gene expression in mitochondria remain unknown. A lack of suitable experimental approaches to modulate mitoGE hampers progress in our understanding. Here I propose a project that takes the next big step towards understanding the mechanisms of mitochondrial gene expression. Our recent work on an in organello system to target mitoGE in a transcript-specific manner provides the bases for the challenging project proposed here, which aims to solve long-standing questions: First, we will dissect mitochondrial transcript interactomes and their spatial orchestration to understand basic principles of RNA abundance, organization in granules, and cross communication. Second, we are now able to investigate translation in the context of the inner membrane with transcript-specific resolution and thereby identify liaising factors involved in ribosome recruitment and membrane insertion and regulation. Third, we will extend our strategy towards an in vivo transcript-specific silencing approach to define retrograde signaling pathways that integrate mitoGE into cellular contexts. The combination of functional analyses carried out in organello and in vivo will provide unprecedented insights into components and mechanism of mitoGE and reveal how two genetically independent systems cooperate to build a functional metabolic pathway able to respond to energetic requirements and challenges.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
37075 Goettingen
Germania