Coordination between mitochondrial protein synthesis and cristae ultrastructure

Challenge: Lack of a tractable model for understanding mitochondrial cristae formation. During development and upon different physiological stresses, mitochondrial cristae undergo remodelling to reprogram mitochondrial function. However, the fundamental research question of how mitochondrial cristae are formed de novo is unknown. The inner mitochondrial membrane and cristae are highly dynamic structures. They undergo continuous fusion and fission events, which are essential for maintaining mitochondrial health. Tracking these dynamic processes in live cells is technically challenging. Solution: This proposal seeks to address the challenge by introducing a practical model system that enables controlled and sequential experimentation on cristae formation. The model will be used to explore the molecular basis and temporal coordination of key factors in de novo cristae biogenesis. Employing super-resolution fluorescence microscopy and single-molecule tracking, we aim to investigate the spatiotemporal organisation and diffusion of individual mitochondrial membrane proteins within live cell cultures. Thereby, we will enhance our understanding of the molecular actors, the mechanisms, pathways, and their spatio-temporal interactions essential to building cristae and modifying membrane morphology. Relevance: The primary challenge addressed in this research proposal is the lack of a model system to understand the initial formation of mitochondrial cristae. We have solved the problem. Now we make use of this model system and state-of-the-art super-resolution microscopy to provide a comprehensive solution applying a unique experimental approach, enabling the systematic study of mitochondrial cristae formation. This aligns very well with the two main BBSRC research priorities: ‘Understanding the rules of life’ and ‘Bioscience for an integrated understanding of health’. We believe that our result may also provide fertile ground for a better understanding of similar membrane biogenesis processes in other domains of life, including plants and bacteria. Further, it has long been established that mitochondrial function plays a central role in embryonic development beyond oxidative phosphorylation. Developing model systems and interrogating fundamental aspects of how mitochondria maintain and influence cristae formation is therefore of utmost importance for understanding not only healthy cellular but also developmental and organismal homeostasis. Potential applications and benefits: Our approach holds promise for providing valuable insights into a completely unresolved aspect of mitochondrial biology by: (i) unravelling fundamental knowledge for how cristae are built; (ii) defining the spatio-temporal organisation of the process and its players; and (iii) our results may benefit research investigating aberrations in inner mitochondrial membrane structure. Variants in proteins responsible for shaping the mitochondrial inner membrane can result in a number of rare and common neurological diseases, including Leigh syndrome, dominant optic atrophy, fatal encephalopathy, and Parkinson's disease. The specific mechanisms by which disease variants cause aberrant cristae formation leading to the onset of these devastating disorders remain largely unexplored.