Structural studies of the human mitochondrial RNA life cycle

Mitochondria maintain an organellar genome that encodes for subunits of the respiratory chain. Its coordinated expression is essential for eukaryotic life, and defects in this process lead to severe disease in humans. Mitochondrial gene expression is carried out by unique dedicated molecular machineries, but the underlying molecular mechanisms remain poorly characterized. During my previous work as a PhD student and Project Leader, I provided the structural basis of human mitochondrial transcription. At the same time, structural insights on mitochondrial translation were reported. However, our understanding of mitochondrial gene expression remains limited due to two fundamental knowledge gaps. First, we lack a molecular understanding of the complex mitochondrial RNA life cycle that takes place in between transcription and translation. Second, we do not know how the different steps of mitochondrial gene expression are functionally coupled, as they are not separated by membranes. With MitoRNA, we propose to take the next big leap towards a mechanistic understanding of mitochondrial gene expression by addressing these blind spots. Using an innovative integrated structural biology approach, we will define the molecular basis of the human mitochondrial RNA life cycle and how it is embedded in the concert of mitochondrial gene expression. In particular, we will investigate the structural basis of various key steps of mitochondrial RNA metabolism in vitro and in situ, and dissect how they are coupled to each other. This ground-breaking work will open up the next frontier in mitochondrial biology by drawing a molecular picture of human mitochondrial RNA metabolism and providing insights into the functional organization of mitochondrial gene expression. In addition, it will also advance methods to study mitochondrial biology from the atomic to the organellar scale.