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It has key parallels with skeletal mineralization; however, the underlying cellular mechanisms responsible are not fully understood. Mitochondrial dynamics regulate both bone and vascular function. In this study, we therefore examined mitochondrial function in vascular smooth muscle cell (VSMC) calcification. Phosphate (Pi)-induced VSMC calcification was associated with elongated mitochondria (1.6-fold increase, p &lt; 0.001), increased mitochondrial reactive oxygen species (ROS) production (1.83-fold increase, p &lt; 0.001) and reduced mitophagy (9.6-fold decrease, p &lt; 0.01). An increase in protein expression of optic atrophy protein 1 (OPA1; 2.1-fold increase, p &lt; 0.05) and a converse decrease in expression of dynamin-related protein 1 (DRP1; 1.5-fold decrease, p &lt; 0.05), two crucial proteins required for the mitochondrial fusion and fission process, respectively, were noted. Furthermore, the phosphorylation of DRP1 Ser637 was increased in the cytoplasm of calcified VSMCs (5.50-fold increase), suppressing mitochondrial translocation of DRP1. Additionally, calcified VSMCs showed enhanced expression of p53 (2.5-fold increase, p &lt; 0.05) and \u03b2-galactosidase activity (1.8-fold increase, p &lt; 0.001), the cellular senescence markers. siRNA-mediated p53 knockdown reduced calcium deposition (8.1-fold decrease, p &lt; 0.01), mitochondrial length (3.0-fold decrease, p &lt; 0.001) and \u03b2-galactosidase activity (2.6-fold decrease, p &lt; 0.001), with concomitant mitophagy induction (3.1-fold increase, p &lt; 0.05). Reduced OPA1 (4.1-fold decrease, p &lt; 0.05) and increased DRP1 protein expression (2.6-fold increase, p &lt; 0.05) with decreased phosphorylation of DRP1 Ser637 (3.20-fold decrease, p &lt; 0.001) was also observed upon p53 knockdown in calcifying VSMCs. In summary, we demonstrate that VSMC calcification promotes notable mitochondrial elongation and cellular senescence via DRP1 phosphorylation. Furthermore, our work indicates that p53-induced mitochondrial fusion underpins cellular senescence by reducing mitochondrial function.<\/jats:p>","DOI":"10.3390\/ijms24021643","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T02:04:45Z","timestamp":1673834685000},"page":"1643","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["p53 Regulates Mitochondrial Dynamics in Vascular Smooth Muscle Cell Calcification"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6745-9818","authenticated-orcid":false,"given":"Kanchan","family":"Phadwal","sequence":"first","affiliation":[{"name":"The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-5896","authenticated-orcid":false,"given":"Qi-Yu","family":"Tang","sequence":"additional","affiliation":[{"name":"The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ineke","family":"Luijten","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-5620","authenticated-orcid":false,"given":"Jin-Feng","family":"Zhao","sequence":"additional","affiliation":[{"name":"MRC Protein Phosphorylation & Ubiquitylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Corcoran","sequence":"additional","affiliation":[{"name":"The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-3069","authenticated-orcid":false,"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1481-9407","authenticated-orcid":false,"given":"Ian G.","family":"Ganley","sequence":"additional","affiliation":[{"name":"MRC Protein Phosphorylation & Ubiquitylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky E.","family":"MacRae","sequence":"additional","affiliation":[{"name":"The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Woodward, H.J., Zhu, D., Hadoke, P.W.F., and MacRae, V.E. 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