Abstract 1072 Unveiling the Nexus of Cellular Quality Control: Exploring the Interplay between Ribosome-Associated Protein Quality Control and Mitochondrial Quality Control Pathways

Eukaryotic cells employ a diverse array of control mechanisms to safeguard the integrity of vital processes, ranging from DNA replication and mRNA translation to the renewal of cellular organelles. Dysfunction within these intricate systems can lead to severe metabolic disorders and diseases. Notably, the hallmark of biological systems lies in their interconnectedness and feedback control mechanisms, and this holds true for cellular quality control systems. Within eukaryotic cells, this interconnectedness extends to the intricate communication between organelles, enabling them to function harmoniously and adapt to ever-changing cellular environments, particularly in response to stressors. While the precise mechanisms governing these communications within cellular quality control systems remain elusive, unraveling the intricate network that interconnects organelles is pivotal for comprehending the foundations of biological systems and elucidating the reasons underlying their collapse in various pathological conditions. Despite ongoing research efforts, a comprehensive understanding of all the routes involved in the communication networks of cellular quality control systems remains a work in progress. Our research, employing Drosophila melanogaster and mammalian cell models, has unveiled a compelling interrelationship between two pivotal cellular pathways: the ribosome-associated protein quality control (RQC) and mitochondrial quality control (MQC) pathways. Our findings underscore that the genes of the RQC pathway can actively regulate the morphology and function of mitochondria and the activity of MQC. We found that RQC factors can interact with FMR1 protein to regulate the assembly and functionality of mitochondrial endoplasmic reticulum contact sites (MERCS). These findings establish a novel link between RQC and MQC pathways, shedding light on their collaborative roles in maintaining cellular health. Furthermore, we discovered that the ribosomal component functions as a central signaling hub that communicates with broader metabolic pathways to precisely reshape mitochondrial homeostasis and cellular energy metabolism in response to ribotoxic stress induced by translation arrest. Our studies also shed light on the regulation of RQC and provide insights into the factors contributing to human diseases linked to proteostasis failure and mitochondrial dysfunction. This work was supported by the NIH (R15AG067470 to Z.W), the Cancer Prevention and Research Institute of Texas (RP210068 to Z.W), the Children's Brain DiseaseFoundation (to Z.W), the Scientific Innovation Program at ModeGene Inc. (U4174ZW202107 to Z.W) and the NUS-AWS cloud credits for research (to B.L).