Author ORCID Identifier
Date Available
5-1-2026
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Arts and Sciences
Department/School/Program
Biology
Faculty
Dr. Chintan Kikani
Faculty
Dr. Jessica Santollo
Abstract
Maintaining cellular energy balance and redox stability is crucial to cell survival, with glutamine metabolism playing a central role. While extensively studied in cancer, where it supports biosynthesis and reduces oxidative stress to promote tumor growth, its function in non-cancerous contexts like tissue development and muscle regeneration remains less understood. A key aspect of stem cell biology is quiescence, a metabolically dormant state that preserves the stem cell pool, yet the mechanisms regulating this state are not fully clear. Here, we identify glutamine metabolism as a critical factor governing myoblast proliferation and quiescence through a metabolic program distinct from that of tumor microenvironments. Suppressing glutamine metabolism induces a quiescence-like state in myoblasts by triggering mitochondrial elongation, membrane depolarization, reduced reactive oxygen species (ROS) production, and cell cycle arrest. This shift is driven by the downregulation of glycolysis and mitochondrial pyruvate oxidation, orchestrated by the activation of Nrf2, a transcription factor that upregulates glutathione biosynthesis, and the mitochondrial glutathione importer Slc25a39. The outcome results in the creation of a reductive stress environment that preserves quiescence, enhances myoblast survival, and maintains stemness. In contrast, glutamine depletion in cancer cells leads to oxidative stress and metabolic collapse. Notably, in muscle stem cells, blocking glutathione biosynthesis or inhibiting Slc25a39 in the absence of glutamine disrupts this metabolic adaptation, thereby restoring mitochondrial function and reactivating proliferation. Importantly, precise regulation of Slc25a39 is found to be essential, as its depletion was found to impair myogenesis in vitro and hinder muscle regeneration in vivo, while its overexpression also impeded myogenesis in vitro. These findings establish mitochondrial glutamine metabolism as a crucial regulatory axis that integrates redox homeostasis with transcriptional and metabolic control of stem cell quiescence. By highlighting metabolic differences between cancer cells and stem cells, this study provides key insights into stem cell fate and suggests potential therapeutic strategies for regenerative medicine and muscle disorders.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.119
Funding Information
This study was supported by a National Institutes of Health grant (R01 3200003096) in 2020.
Recommended Citation
Kelly, Brian, "THE ROLE OF METABOLIC GATE KEEPERS IN CELL FATE DECISION MAKING" (2025). Theses and Dissertations--Biology. 112.
https://uknowledge.uky.edu/biology_etds/112
