Mitochondrial liquid-liquid phase separation in Alzheimer's disease

PROJECT SUMMARY In Alzheimer's disease, abnormalities in the morphology, transport, and functions of mitochondria are prevalent. Mitochondria are cellular organelles that generate energy to fuel cellular metabolism. Toxic Aβ42 is known to concentrate in mitochondria. However, how Aβ42 affects crucial mitochondrial processes that maintain mitochondrial health is still unclear. The long-term objective is to contribute to developing mechanism- based treatment strategies for Alzheimer's disease. The overarching goal of this application is to identify the mechanisms responsible for Aβ42's effects on the regulation of mitochondrial gene expression after transcription and mitochondrial dysfunction in a basic cell model. The central hypothesis is that Aβ42 interferes with mitochondrial liquid-liquid phase separation, causing morphological and functional mitochondrial defects in Alzheimer's disease. The rationale for the proposed research is that a mechanism-based determination of Aβ42's role in mitochondrial dysfunction will provide new opportunities for developing novel strategies to intervene in Alzheimer's disease. To attain the overall objective, the following two specific aims will be pursued: (Aim 1) Investigate the impact of Aβ42 on mitochondrial ribonucleoprotein granule dynamics in mitochondria.; (Aim 2) Optogenetic control of Aβ42 and mitochondrial ribonucleoprotein granules in mitochondria. At the completion of these aims, this project will provide insights into how to maintain mitochondrial health by modulating the mitochondrial liquid-liquid phase separation in Alzheimer's disease.