Design, Generation and Initial Characterization of knock out mice for MIEF Mitochondrial Factors

Mechanical forces play a critical role in cellular behaviour, influencing processes such as development, homeostasis, and disease progression. Recently, it has been shown that mechanical cues impact mitochondrial morphology and dynamics and this in turn orchestrates downstream responses. In our lab we elucidated the role of mitochondria in coordinating the biological responses to ECM changes. Our studies demonstrated the central role of the phosphorylation of the fission factor Mief1 to limit mitochondrial fission when cells develop high actomyosin tension. This mitochondrial remodelling, consequently, modifies the activity of different transcription factors (TFs), such as YAP, SREBP1/2 and NRF2. To validate this link between mitochondrial dynamics, TFs activity and metabolic rewire in vivo, we generated transgenic mice mutant or knockout for Mief factors using different strategies. In this thesis, we crafted a strategy and set up the tools to screen the mice. Moreover, we isolated lung fibroblast to validate the loss of function of the Mief2 knockout and the recombination of the conditional alleles leading to the expression of the mutant Mief1. Our goal is to propose a new in vivo tool to study the link between mitochondrial dynamics and mechanotransduction. Our study would help better understand the role of phosphorylation of Mief1 in mechanotransduction in physiological and pathological conditions. In fact, changes in mitochondrial morphology occur in physiological processes, such as proliferation, differentiation and metabolism rewiring and even in patients affected by neuropathies and neurodegenerative diseases.