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Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD\n                    <jats:sup>+<\/jats:sup>\n                    \/NADH ratio, and reduced CI function in BHPrS1 cells. Thus, ZC3H4 loss promotes mitochondrial dysfunction to drive pathophysiologic changes in the stromal compartment that are features of the aging prostate.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08027-8","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:07:16Z","timestamp":1761052036000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0879-2394","authenticated-orcid":false,"given":"Teresa T.","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9173-148X","authenticated-orcid":false,"given":"Mia J.","family":"Carrarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1838-0024","authenticated-orcid":false,"given":"Livianna K.","family":"Myklebust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5460-3418","authenticated-orcid":false,"given":"Kegan O.","family":"Skalitzky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"El-Khoury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J.","family":"Sipula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3822-0469","authenticated-orcid":false,"given":"Alexander","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal","family":"Soman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nnamdi","family":"Ihejirika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma R.","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Jurczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Ricke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7662-4886","authenticated-orcid":false,"given":"Donald B.","family":"DeFranco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3840-1662","authenticated-orcid":false,"given":"Laura E.","family":"Pascal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"8027_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/gerona\/glad222","volume":"79","author":"AE Adrian","year":"2024","unstructured":"Adrian AE, Liu TT, Pascal LE, Bauer SR, DeFranco DB, Ricke WA. 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Ethical approval for de-identified primary human BPH prostate stromal cells TP18S317 derived from BPH patient tissue specimens was obtained from University of Pittsburgh Institutional Review Board (IRB#20090026) with patient consent. Ethical approval for the tissue microarray was obtained from the University of Wisconsin Institutional Review Board (IRB# 2012-1033, IRB# 2012-0508). Tissues for the pTMA were obtained from a pathology archive and were used for diagnostic purposes, so patient consent was not deemed necessary. Patient identifying information was anonymized and de-identified prior to receipt of tissues for all specimens used in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"741"}}