Principal Investigator
Unraveling the intricate dance of mitochondrial dynamics: we explore fundamental signaling pathways occurring in cell division, shedding light on the overlooked impact of defective mitotic regulation of mitochondrial functions in aging and diseases.
Abnormalities in the regulation of mitochondrial dynamics impact on a plethora of cellular functions – ranging from autophagy to cell cycle progression – and are hallmarks of numerous disorders associated with ageing.
Our research aims to elucidate the signaling cascade that initiates the fragmentation of the mitochondrial network and the loading of mitochondria on the actin cytoskeleton during cell division. In fact, how the cell cycle machinery is actively regulating the reorganization, distribution and segregation of mitochondria during mitosis remains a fundamental and still open question in cell biology. Furthermore, given the limited knowledge of the impact of defective mitochondrial dynamics on mitotic progression and chromosome inheritance, the possible physiological outcomes are often neglected in the context of mitochondrial diseases and ageing, although they may substantially contribute to the development of pathological phenotypes and senescence.
Our research methodology relies on experimental approaches designed to overcome the limitations of conventional biochemical reconstitution, which often confines observations to in vitro settings that are not directly indicative of cellular physiological conditions. Instead, we employ direct investigations in living human cells based on predictions derived from in vitro assays. In fact, we believe that extrapolating specific sub-processes occurring at mitochondria in mitotic cells and reproducing them in a simplified and controlled system in vitro is key to advance our understanding of these fundamental and still overlooked signaling pathways.
Our goal is to address these two central questions:
We will pursue a dual approach: i) recreate the protein network responsible for governing the assembly of the mitochondria fission machinery and the connection of mitochondria to actin filaments during mitosis in vitro, to identify essential interactions and post-translational modifications; ii) establish a cellular system to examine the impact of precisely depleting mitochondrial fission during mitosis on mitotic progression and chromosome segregation. Through a comparative analysis of the outcomes from these diverse approaches, we aim to pinpoint the specific regulatory step sufficient for these processes to fail and disrupt normal mitotic progression.
Mitotic errors result in aneuploidy, a major driver of tumorigenesis, and can activate cellular inflammation and senescence pathways. We strongly believe in the intricate interconnectedness of the cell cycle, chromosome inheritance, and mitochondrial dynamics, with yet-to-be-discovered cross-talks and interdependencies. Thus, the successful outcome of our research constitutes a unique resource to build a comprehensive functional understanding of these disparate but inherently connected processes that will shed light on the etiology of numerous human pathologies.
Principal Investigator