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The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation.<\/jats:p>","DOI":"10.1371\/journal.pgen.1012330","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:42:33Z","timestamp":1791481353000},"page":"e1012330","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-3907","authenticated-orcid":true,"given":"Vinoth","family":"Sigamani","sequence":"first","affiliation":[{"name":"University of Tennessee Health Science Center","place":["Memphis, Tennessee, United States of America"],"department":["Department of Pathology and Laboratory Medicine, College of Medicine and the Center for Cancer Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd","family":"Yousuf","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center","place":["Memphis, Tennessee, United States of America"],"department":["Department of Pathology and Laboratory Medicine, College of Medicine and the Center for Cancer Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1600-6768","authenticated-orcid":true,"given":"Daniel L.","family":"Johnson","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center","place":["Memphis, Tennessee, United States of America"],"department":["Molecular Bioinformatics Core and the University of Tennessee Health Science Center Office of Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Strahl","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Biochemistry and Biophysics, and the Lineberger Comprehensive Cancer Center"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4519-4470","authenticated-orcid":true,"given":"R. 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