Structure and Function of Molecular Machines

Structure and Function of Molecular Machines

Our research is aimed at understanding the structure and function of molecular machineries in eukaryotic cells and organelles. For this, we combine structural biology methods such as single-particle cryo-electron microscopy, X-Ray crystallography and cryo-electron tomography with biochemical and biophysical approaches to unravel the mechanistic basis of cellular processes.

A particular focus of our research lies on mitochondria. These are double-membrane enclosed organelles within eukaryotic cells that are often referred to as the 'powerhouses' of the cell, because the respiratory chain at their inner membrane provides the majority of chemical energy required for life. In addition, they play important roles in other processes such as metabolism, signaling and immune defense. Not surprisingly, impaired mitochondrial function is associated with ageing as well as with a number of human diseases. As a remainder of their endosymbiotic origin, mitochondria maintain their own genome which encodes for essential components of the respiratory chain. In order to form functional complexes, these subunits must assemble with a large number of nuclear-encoded subunits that are imported into the organelle. Therefore, the expression of mitochondrial genes needs to be regulated as well as coordinated with nuclear gene expression to ensure proper mitochondrial function. The importance of this process is underscored by the fact that defects in mitochondrial gene expression lead to severe disease in humans. Mitochondrial gene expression is carried out by a set of dedicated molecular machineries, which include a mitochondrial RNA polymerase and a mitochondrial ribosome. Over the course of evolution, this apparatus has adopted features found in nuclear, bacterial, and viral gene expression systems, thus making it truly unique. Despite its fundamental role in cellular function, the molecular mechanisms underlying mitochondrial gene expression and how it is regulated in response to varying cellular needs are not well understood. 

The research in our group addresses fundamental open questions in mitochondrial molecular biology. Our goal is to obtain a molecular understanding of how the human mitochondrial genome is expressed, how this process is regulated and coordinated, and how it is embedded in a cellular context. To achieve this, we study both the molecular mechanisms underlying mitochondrial gene expression as well as how individual processes are intertwined and organized within the organelle. By combining in vitro (single-particle cryo-EM, X-Ray crystallography) with in situ (cryo-electron tomography) structural biology, we aim to dissect these processes from the atomic to the organellar scale. In the long term, this will provide important molecular insights into mitochondrial function in human health and disease.

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