Jerome Avellaneda


Investigating mechanisms of mitochondrial dynamics during flight muscle development

Muscle morphogenesis is a complex multi-step process that results in highly specialised cells containing contractile myofibrils and energy producing mitochondria. Myofibrils are long chains of a succession of stereotyped nanomachines called sarcomeres that contract by pulling on actin filaments by central myosin filaments at the expense of ATP, mainly provided by an efficient mitochondria network. Recent studies have elucidated how contractile sarcomeres are assembled during myofibrillogenesis. However, how muscle cells regulate and specialise their mitochondria to support the high energy demands of sarcomere function remains largely unknown. It is particularly unclear how the myofibril and mitochondria morphogenesis are coordinated. I addressed these questions during my thesis by taking advantage of the Drosophila melanogaster flight muscle, a well characterised model of myofibrillogenesis. I have shown that mitochondrial organisation is genetically instructed and depends on the muscle subtype. In the flight muscles, mitochondria and nuclei are deformed by the mechanical pressure applied by the myofibrils allowing close contact of myofibrils to the surrounding mitochondria and, as a consequence, individualisation of neighbouring myofibrils. This organization requires a process of mitochondrial intercalation, which is dependent on microtubule-based transport during myofibrillogenesis. Mitochondrial intercalation induces a transcriptional shift necessary for normal muscle development via a proposed mechanical feedback mechanism. I also contributed to the characterisation of the role of a new nuclear mechanosensitive gene CG32121, which we named tono. We found a role for Tono in myofibril and mitochondria maturation during the development of flight muscles, proposing a mechanosensitive liquid-liquid phase separation as the key mechanism. My work has shown that mitochondria remodelling is essential for muscle development and has highlighted the importance of tension exerted by the developing myofibrils in coordinating mitochondria with myofibril maturation.