Subject Area
Biochemistry, Biological Sciences, General, Cell Biology, Genetics, Life Sciences, Molecular Biology
Abstract
In eukaryotic cells, the intricate interplay between cellular quality control mechanisms is crucial for maintaining homeostasis and safeguarding the integrity of vital processes, spanning from macromolecule synthesis to the renewal of entire cellular organelles.
Disruption of these networks can lead to severe diseases such as metabolic disorders, underscoring the interconnected nature and feedback control mechanisms inherent in biological systems, including cellular quality control systems. This interconnectedness extends to the intricate communication between organelles, enabling coordinated functioning and adaptation to changing cellular conditions, particularly in response to stressors.
While the exact mechanisms governing these communications within cellular quality control systems remain unclear, unraveling the complex network connecting organelles is essential for understanding the fundamentals of biological systems and uncovering the causes of their breakdown in various pathological conditions. Despite ongoing research endeavors, fully grasping all the pathways involved in the communication networks of cellular quality control systems remains a work in progress.
In this study, utilizing models of Drosophila melanogaster and mammalian cells has revealed a previously unrecognized nexus between two fundamental cellular quality control pathways: the ribosome-associated protein quality control (RQC) and the mitochondrial quality control (MQC). We demonstrated that two key proteins in the ribosomal 40S subunit recycling pathway—USP10/Usp10 and G3BP1/rin, which are components of RQC—play a crucial role not only in ribosomal 40S subunit recycling but also in broader cellular processes beyond the ribosomal context. We demonstrated their role in modulating mitochondrial dynamics and positively tuning the MQC pathway in both Drosophila and mammalian cells. The ribosomal 40S subunit recycling factors bind to the fission-fusion machinery at the dynamic hotspots on mitochondria, regulating the assembly and function of the Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs). The overexpression of USP10 and G3BP1 induces changes in the mTOR pathways, central players in cellular metabolic control, suggesting a potential interplay between RQC and broader cellular stress response mechanisms.
Intriguingly, our genetic screens in Drosophila uncovered modifiers, such as dZnf598 (a ribosomal collision sensor) and Fmr1 (associated with Fragile X syndrome), adding layers of complexity to the interconnected regulation of RQC and MQC. Furthermore, our exploration extends to the ERMCSs, revealing genetic, physical, and functional interactions with components of the 40S ribosomal recycling complex, including IP3R, VDAC, and MCU.
These findings position RQC and MQC on a continuum within the broader cellular quality control network. The 40S ribosomal subunit recycling complex emerges as a dynamic hub, orchestrating communication with other signaling pathways to swiftly respond to changes occurring near the ERMCSs junctions. Such adaptability is essential for cellular responses to proteostasis stress associated with aging and various environmental stressors.
This study deepens our understanding of the multifaceted roles played by the 40S ribosomal subunit recycling complex and its associated proteins, USP10/Usp10 and G3BP1/rin, in the intricate web of cellular quality control. It shed light on the molecular underpinnings of RQC regulation highlighting its significance beyond ensuring translation fidelity. Notably, RQC emerges as an integral component of broader cellular stress responses, offering potential insights into the pathogenesis of human diseases marked by proteostasis failure and mitochondrial dysfunction.
Degree Date
Spring 5-11-2024
Document Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
Advisor
Dr. Zhihao Wu
Number of Pages
181
Format
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Recommended Citation
Tahmasebinia, Foozhan, "Unveiling the Nexus of Cellular Quality Control: Exploring the Interplay Between Ribosome-Associated Protein Quality Control and Mitochondrial Quality Control Pathways" (2024). Biological Sciences Theses and Dissertations. 23.
https://scholar.smu.edu/hum_sci_biologicalsciences_etds/23
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