Inter-Organelle UPR Coordination and Cellular Proteostasis

About This Grant

Project Summary/Abstract This research project delves into the complex biological phenomenon of organelle-specific Unfolded Protein Responses (UPRs) in eukaryotic cells, focusing on their role in maintaining proteostasis under stress conditions prevalent in aging. We aim to understand the intricate communication and coordination mechanisms between UPRs in various cellular compartments, such as mitochondria, the endoplasmic reticulum, and the cytosol. A key aspect of our study is the interplay between lipid metabolism and these protein-folding processes, an underexplored area in cellular biology. Lipid dyshomeostasis is a major contributor to a range of devastating diseases, including neurodegenerative diseases, cardiovascular disease, diabetes, and cancer. Despite extensive research, the role of lipids in regulating cellular homeostasis remains unclear. Our long-term goal is to understand how cells utilize different organelle stress responses to maintain homeostasis under various stressors. The overall objective of this project is to explore the connection between lipid homeostasis and proteostasis and their interplay in the context of organelle-to-organelle communication. Our central hypothesis is that the relative cardiolipin-to-ceramide ratio is crucial for communication between stress response pathways in the mitochondria, ER, and cytosol. This hypothesis is based on preliminary data generated from well- characterized C. elegans and mammalian cell culture systems. Our previous research found that a branch of unfolded protein response in mitochondria (UPRmt), triggered by mitochondrial protein folding stress, activated the cytosolic unfolded protein response (UPRcyt) while inhibiting the unfolded protein response in the ER (UPRER) to increase cellular resistance to proteotoxic stress. We also discovered a novel mechanism of stress response regulation involving the opposing effects of two lipids, cardiolipin and ceramides, on proteostasis. Using both C. elegans and mammalian cell culture systems, this project will employ cutting-edge techniques in proteomics, lipidomics, and advanced imaging to provide an efficacious and comprehensive view of these cellular processes. For the next five years, the research program aims to map pathways and interactions in organelle-specific UPRs and determine how these processes are spatiotemporally regulated under proteostasis stress, offering novel insights into the cellular maintenance of protein homeostasis and its impact on cellular and organismal health.