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Therefore, 12\u00a0week-old Sirt3-deficient mice were used as cardiac hypertrophy model. The morphological changes of cardiac muscle fibers and the ultra-structure changes of mitochondria were detected by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Then, multi-omics approach was used to analyze the differently expressed genes and different metabolites. Key genes and metabolites were scrutinized through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, in vitro studies examining the effects of Sirt3 knockdown on H9C2 cells, including intracelluler and mitochondrial reactive oxygen species (ROS) and calcium, and mitochondrial membrane potential (MMP). Western blot and qPCR were used to verify the differently expressed genes. The hearts of Sirt3-deficient mice increased myofiber thickness, and altered mitochondrial morphology. Sirt3 deficiency induced mitochondrial dysfunction was promoted by an inhibition of the translation of oxidative phosphorylation (OXPHOS) complex subunits. Multi-omics profiling implicated CD38 as a major NAD consumer and linked the metabolites of CD38 to cAMP signaling pathways. Furthermore, in vitro studies examining H9C2 Sirt3 knockdown showed an increase in intracellular and mitochondrial ROS levels, a decrease in MMP, and promoted MCU expression and mitochondrial calcium overload. However, CD38 inhibitors effectively attenuated Sirt3 knockdown-induced elevations in intracellular and mitochondrial ROS levels, dissipation of mitochondrial membrane potential, and mitochondrial calcium overload, thereby restoring mitochondrial function. In summary, the Sirt3\u2013CD38 axis induces mitochondrial dysfunction in hypertrophied heart by regulating mitochondrial calcium overload. These findings will aid in providing new ideas for the prevention and treatment of age-related cardiac hypertrophy.<\/jats:p>","DOI":"10.1186\/s40001-025-03211-0","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T14:07:34Z","timestamp":1760450854000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Sirt3\u2013CD38 axis induces mitochondrial dysfunction in hypertrophied heart by regulating mitochondrial calcium overload"],"prefix":"10.1186","volume":"30","author":[{"given":"Jia","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"issue":"9","key":"3211_CR1","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.3390\/biom13091409","volume":"13","author":"H Dridi","year":"2023","unstructured":"Dridi H, Santulli G, Bahlouli L, Miotto MC, Weninger G, Marks AR. 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