Drp1-induced mitochondrial fission controls cortical astrocyte organization (2024)
Undergraduate: Sprihaa Kolanukuduru
Faculty Advisor: Shveta Parekh
Department: Duke Cell Biology, Psychology and Neuroscience
Mitochondrial homeostasis is essential to proper brain development and dysfunctional mitochondria are implicated in multiple neurodevelopmental disorders. Mitochondrial function and localization is regulated by mitochondrial fission, fusion, and trafficking, collectively referred to as mitochondrial dynamics, a process that is particularly important in highly branched cells of the brain. Astrocytes are glial cells characterized by their complex branched morphology that allows them to perform many functions such as inducing synaptogenesis in the developing cortex. Cortical astrocytes are organized in nonoverlapping territories in a phenotype described as tiling, which enables them to form a network and communicate over long distances by gap junction coupling. Tiling is a hallmark of astrocyte maturity and is lost in disease, suggesting tiling is imperative to astrocyte development and function. However, the molecular mechanisms of how astrocytes establish tiling during development are not well understood. Past research in the Eroglu Lab has shown that early postnatal knockdown (KD) of Drp1, the regulator of mitochondrial fission, in astrocytes in the mouse cortex leads to astrocytes clustering. Therefore, we hypothesized that Drp1-induced mitochondrial fission regulates astrocyte organization in the mouse cortex. We found that sparse Drp1 KD in astrocytes induces clustering into adulthood up to 6-month-old mice, indicating Drp1 control of astrocyte organization is not a transient developmental mechanism. Furthermore, we uncovered that Drp1 KD astrocyte clusters are multi-cell clusters and have disorganized cell somas, confirming Drp1 controls the organization of astrocytes. Additionally, Drp1 KD astrocyte clusters have decreased Connexin 43 gap junction protein expression, suggesting they have impaired gap junction coupling. Lastly, we found that astrocyte-specific conditional KO of Drp1 results in reduced astrocyte coverage in the cortex coupled with heterogeneous upregulation of GFAP, a marker of astrocyte dysfunction. These findings indicate that Drp1 controls astrocyte organization and function and underscore the importance and therapeutic potential of mitochondrial fission in the proper development of astrocytes.