A single faulty protein, DRP1, can stop brain cells from dividing their energy-producing mitochondria, leading to lethal neurological conditions in children. Mitochondria must constantly split and rejoin to stay healthy, especially in neurons that never divide and have high energy demands. DRP1 is the protein that pinches mitochondria in two, but when it is mutated, the process fails. This research will introduce known disease-causing DRP1 mutations into human stem cells, grow them into mixed cultures of neurons and support cells, and watch what goes wrong at the molecular level. The team will also investigate mysterious liquid-like clumps of DRP1 that form inside cells—their function is unknown, but they may be key to understanding how the protein normally works. This is fundamental science. It will not produce a treatment tomorrow. But it will reveal the precise chain of events that turns a single genetic typo into catastrophic brain damage. That mechanistic understanding is the necessary foundation for designing drugs that could one day restore mitochondrial division in patients. Similar fundamental work on mitochondrial dynamics has already opened paths to therapies for Parkinson’s disease and rare metabolic disorders.
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Mitochondria play a central role in cellular bioenergetics, and act as important metabolic and signalling hubs controlling diverse biological processes. The dynamic structure of highly interconnected mitochondrial networks is regulated by specialised mitochondrial fission and fusion proteins. Mitochondrial network plasticity is particularly important in post-mitotic neurons, which require constant mitochondrial rejuvenation and long-distance mitochondrial trafficking to meet their high metabolic demands. Therefore, it is not surprising that impaired mitochondrial fission and fusion is associated with a diverse spectrum of pathological conditions, including inherited multisystemic mitochondrial diseases and neurodegenerative disorders. Dynamin-related protein 1 (DRP1) is the key regulator of mitochondrial fission, and pathogenic DRP1 variants cause lethal neurological conditions. The location of DRP1 can be diffuse in the cytoplasm, self-assembled in distinct puncta on organelles destined to undergo scission or in puncta that represent dynamic liquid-liquid phase separated (LLPS) biomolecular condensates with unknown function. Multiple molecules of DRP1 self-assemble into ring structures around mitochondria and execute organellar division following GTP-hydrolysis-dependent structural changes. The mechanisms that hallmark DRP1-related neuropathology require further exploration in physiologically and disease relevant models. My research seeks to identify mechanisms that regulate DRP1-dependent processes in human neural cultures. CRISPR/Cas9-mediated knock-in of pathogenic DRP1 variants into human induced pluripotent stem cells will enable the generation of disease-specific neural co-culture models. This research will explore the biological significance of LLPS DRP1 puncta and the impact of DRP1 variants on self-assembly and subcellular distribution in neuronal-astrocytic co-cultures, using unique iPSC-derived models and cutting-edge bioimaging, biochemical and biophysical approaches.
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