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Entry into and exit from this arrest, known as \u201cquiescence,\u201d is governed by the inhibition of mTORC1. The pharmacological suppression of mTORC1 with rapamycin prevents quiescent stem cells from re-entering the cell cycle and impairs tissue regeneration. Rapamycin holds great therapeutic promise in preventing tumor regrowth from dormant cancer stem cells. Yet the extent to which genetic background impacts the known variation in the pharmacological response of rapamycin remains unknown. Here, we show that natural genetic variation across the Drosophila Genetics Reference Panel (DGRP) drives substantial differences in the rapamycin-mediated suppression of post-IR quiescence and regeneration. To define the basis of this differential sensitivity, we examined mitochondrial turnover and DNA damage repair\u2014processes controlling IR-induced dormancy. Our analyses reveal that variation in rapamycin sensitivity is more strongly associated with differences in mitochondrial dynamics than with DNA damage response following radiation. Together, these findings demonstrate that genetic background is a critical determinant of rapamycin efficacy and identify mitochondrial regulation as a key mechanism underlying differential therapeutic response.<\/jats:p>","DOI":"10.3390\/cells15030236","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T12:41:16Z","timestamp":1769431276000},"page":"236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Genetic Variation Impacts Stress-Induced Quiescence and Regeneration in Response to Rapamycin"],"prefix":"10.3390","volume":"15","author":[{"given":"Sahiti","family":"Peddibhotla","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Gonzaga","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tricia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasha","family":"Goel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4268-7686","authenticated-orcid":false,"given":"Benjamin R.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E. L.","family":"Promislow","sequence":"additional","affiliation":[{"name":"Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5588-4531","authenticated-orcid":false,"given":"Hannele","family":"Ruohola-Baker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.stem.2020.09.011","article-title":"Tissue Stem Cells: Architects of Their Niches","volume":"27","author":"Fuchs","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.stem.2011.10.004","article-title":"Maintaining tissue homeostasis: Dynamic control of somatic stem cell activity","volume":"9","author":"Biteau","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/nm.3651","article-title":"Stem Cell Aging: Mechanisms, Regulators and Therapeutic Opportunities","volume":"20","author":"Oh","year":"2014","journal-title":"Nat. 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