Project description
Watching mitochondrial membrane formation in action for the first time
All the cells of the body require energy to do their jobs. Mitochondria, organelles found abundantly in every cell, are the so-called powerhouses. They produce a molecule that releases the energy required to support cellular functions. Mitochondrial dysfunction is associated with many varied diseases and conditions. MitoCRISTAE is applying new high-tech methods to study the development of convoluted membranes in mitochondria, whose dynamically changing structure has recently been linked to the functioning of the energy production pathway. In studies only recently possible, the team plans the pioneering investigation of membrane development over time to understand mitochondrial structure and function in health and disease.
Objective
Mitochondrial cristae biogenesis is an enigma ever since the first imaging of mitochondria, the ‘powerhouses’ of eukaryotic cells, by electron microscopy in the 1950s. The mitochondrial cristae, dynamic and structurally conserved invaginations of the mitochondrial inner membrane, are essential for respiratory ATP generation. Thereby, the form and function of the mitochondrial inner membrane are deeply intertwined. Indeed, irregular or disturbed cristae morphologies are believed to cause numerous human diseases, including neurodegeneration, cardiomyopathies, metabolic disorders and cancer.
Previous approaches to study cristae biogenesis have relied primarily on the use of 2D electron microscopy and biochemistry to analyse mutant cells defective in cristae formation. Based on striking pilot experiments, we propose to study cristae biogenesis by a radically different approach. We will induce synchronous cristae development in gene-edited cell lines initially defective in cristae formation. We will then follow de novo cristae biogenesis over time by combining a series of enabling approaches, including live cell and MINFLUX super-resolution microscopy, 3D (cryo) electron microscopy, label-free (SWATH) mass spectrometry, and single molecule counting. These technologies have just emerged in the last few years, and thus this proposal would not have been possible a few years ago. The primary aim of this proposal is to establish a deep, comprehensive and quantitative understanding of cristae biogenesis in human cells. Using theses insights, we will also investigate the effects of mutations in mitochondrial proteins associated with human diseases on cristae biogenesis.
Altogether, if successful, the outcome will represent a paradigm shift in our knowledge of how mitochondrial ultrastructure in healthy and diseased cells is generated and maintained. Our findings might spark innovative and novel strategies for the treatment of devastating human mitopathies.
Fields of science
- natural sciencesbiological sciencesneurobiology
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- medical and health sciencesclinical medicineoncology
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
37075 Goettingen
Germany