Date of Award
2026
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Elaine Fuchs
Abstract
Stem cells are sustained within specialized niches where environmental cues, including oxygen availability, shape their ability to balance proliferation and differentiation. The epidermal stem cell (EpSC) niche is physiologically hypoxic, yet how EpSCs adapt to the metabolic consequences of low oxygen remains poorly understood. In this thesis, I identify the mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) as a critical safeguard against the toxic accumulation of the hypoxia-induced metabolite L-2-hydroxyglutarate (L-2HG). Using genetic deletion and metabolite supplementation approaches, I demonstrate that L- 2HG accumulation impairs EpSC proliferation, prolongs the cell cycle, and induces DNA damage. These defects are exacerbated under hypoxia and partially rescued by over-expression of L2HGDH, establishing L-2HG as a key mediator of the hypoxic response. RNA sequencing of L2HGDH-deficient EpSCs revealed broad transcriptional suppression, particularly of genes involved in mitotic progression and DNA repair, consistent with the observed proliferation defects. While L-2HG can inhibit αKG-dependent dioxygenases, changes in histone methylation were modest, suggesting that other metabolic consequences of L2HGDH loss. Metabolomic profiling of L2HGDH deficient EpSCs uncovered broad metabolic alterations including reduced TCA cycle intermediates, and an increased SAM/SAH ratio, pointing to impaired mitochondrial function and change in methylation capacity. In addition, an increased redox species was observed, which might be underlying reason of DNA damage. Together, these findings reveal that L2HGDH is indispensable for preserving EpSC proliferation and genome integrity by preventing toxic L-2HG accumulation. More broadly, this work highlights how metabolic adaptation to hypoxia is essential for stem cell function and suggests that disruption of this pathway underlies the developmental and pathological features of L-2-hydroxyglutaric aciduria.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Izgi, Irem Basak, "Metabolic Adaptation to Hypoxia in Epidermal Stem Cells: The Critical Role of L-2- Hydroxyglutarate Dehydrogenase in Skin Development" (2026). Student Theses and Dissertations. 859.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/859
Comments
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy