{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:28:46Z","timestamp":1789439326195,"version":"build-2803163510"},"reference-count":88,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Handok Inc.\n\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/00exehz38"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The progressive decline in functional \u03b2-cell mass in Type 2 Diabetes (T2D) is increasingly recognized not as a simple apoptotic loss, but as a complex erosion of cellular identity termed \u201cdedifferentiation.\u201d Central to this phenotypic shift is the metabolo-epigenetic axis, where mitochondria act as the primary sensing hub, transducing nutrient flux into biochemical signals that govern the chromatin landscape. This review synthesizes current evidence on how mitochondrial metabolites\u2014including Acetyl-CoA, \u03b1-ketoglutarate, and NAD+\u2014serve as obligatory co-factors for the epigenetic machinery. We explore how chronic metabolic stress triggers a \u201cSystemic epigenetic destabilization,\u201d leading to the loss of lineage-specific markers and the formation of persistent \u201cmetabolic scars.\u201d Furthermore, we discuss the clinical implications of these changes, specifically regarding the phenomenon of metabolic memory and the molecular limits of \u03b2-cell reversibility. By integrating foundational transcriptional studies with emerging epigenomic data, we propose that targeting the mitochondrial\u2013epigenetic axis offers a strategic window for re-differentiating failing \u03b2-cells and restoring glycemic homeostasis.<\/jats:p>","DOI":"10.3390\/cells15070595","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:33:33Z","timestamp":1774622013000},"page":"595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mitochondria as Epigenetic Regulators of \u03b2-Cell Identity and Plasticity: A Metabolo-Epigenetic Perspective"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-1338","authenticated-orcid":false,"given":"YongKyung","family":"Kim","sequence":"first","affiliation":[{"name":"Institute of Medical Science, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2337\/diabetes.52.1.102","article-title":"Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes","volume":"52","author":"Butler","year":"2003","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.cell.2012.07.029","article-title":"Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure","volume":"150","author":"Talchai","year":"2012","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1210\/jc.2015-2860","article-title":"Evidence of beta-Cell Dedifferentiation in Human Type 2 Diabetes","volume":"101","author":"Cinti","year":"2016","journal-title":"J. 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