Projektbeschreibung
Mechanistische Erkenntnisse zur mitochondrialen Genexpression
Neben der DNS im Zellkern enthalten eukaryotische Zellen auch mitochondriale DNS, die Untereinheiten der Enzyme für die Elektronentransportkette kodiert. Obwohl das eindeutig die Bedeutung der mitochondrialen Genexpression für den Zellstoffwechsel zeigt, verfügen wir bisher über kaum mechanistische Erkenntnisse darüber, wie sie erreicht und reguliert wird. Es ist bereits bekannt, dass die mitochondriale Gentranslation durch im Zellkern kodierte Faktoren reguliert wird. Das über den Europäischen Forschungsrat finanzierte Projekt MiXpress schlägt die Untersuchung der unterschiedlichen Schritte im Ablauf der mitochondrialen Genexpression vor. Dabei liegt der Schwerpunkt auf der Wechselwirkung mit im Zellkern kodierten Bestandteilen, um so zu verstehen, wie Zellen auf Energieanforderungen reagieren.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
37075 Goettingen
Deutschland