Dysregulation of Mitochondrial Dynamics in Sepsis

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Project Summary While recent literature suggests that p53, a regulator of apoptosis, is crucial in the development of sepsis- induced mitochondrial failure, the mechanistic underpinnings behind this finding are not clearly delineated. My preliminary studies have demonstrated that sepsis mediated mitochondrial localization of p53 propagates mitochondrial failure by interacting with dynamin-related protein 1 (Drp1) and promoting Drp1- fission 1 (Fis1) mediated mitochondrial fragmentation. Furthermore, increased mitochondrial localization of p53 in sepsis leads to an accumulation of damaged mitochondria by interacting with, and blocking, key mediators of mitophagy (process necessary for clearance of damaged mitochondria). Importantly, when p53 accumulation is blocked in a cell culture model of sepsis, Drp1 activation is decreased, excessive mitochondrial fission is abrogated and mitochondrial function is rescued. Taken together, my findings suggest that mitochondrial localization of p53 contributes significantly to mitochondrial failure by promoting excessive fission and dysfunctional mitophagy. However, the mechanism through which p53 interacts with key mediators of fission and mitophagy is not clearly understood. Accordingly, using cutting edge methods in chemical biology, this project will: 1) characterize the interaction site between p53 and key mediators of pathologic fission and mitophagy and 2) develop rationally designed peptides that abrogate the pathologic effects of p53 on the mitochondria. To achieve these goals proposed aims of this project are: AIM 1 (K99): Characterize the direct and indirect role of Drp1 on sepsis mediated p53 stabilization and mitochondrial localization. AIM 2 (R00): Determine the consequences of p53 localization patterns on sepsis induced mitophagy and characterize the interaction site between p53 and key mediators of mitophagy. , the AIM 3 (R00): Develop novel protein-protein inhibitors that interfere with pathologic interaction between p53 and mitochondria in sepsis. The proposed project is significant as it will reveal novel mechanistic pathways which contribute to end organ failure in sepsis by defining the link between excessive p53 activation and altered mitochondrial fission and mitophagy. Furthermore, this project aligns with my long-term goal to become an independent physician scientist, identifying therapeutic targets in mitochondrial pathways which abrogate sepsis-induced end organ failure in children. The training program in the K99-phase will further my technical skills and knowledge in chemical biology (aim 1). The proposed R00-phase will provide novel information regarding mitochondrial adaptors of p53 and develop rationally designed peptides that inhibit pathologic p53 - mitochondria interactions (aim 2&3).