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Using high-resolution respirometry, we investigated the role of VEGF in optimizing mitochondrial oxidative phosphorylation efficiency in neuronal-like cells. Our findings indicate that VEGF enhances coupling efficiency for ATP synthesis by reducing the uncoupled respiration, a process involved in mitochondrial dysfunction and neurodegeneration, as observed in Parkinson\u2019s disease (PD). To investigate the VEGF relevance in PD, we exposed differentiated SH-SY5Y cells to MPP\n                    <jats:sup>+<\/jats:sup>\n                    , a toxin inducing a PD-like phenotype. Both VEGF and a mimic peptide (VEGF\n                    <jats:sub>73-101<\/jats:sub>\n                    ) reduced MPP\n                    <jats:sup>+<\/jats:sup>\n                    -induced uncoupled respiration, mitochondrial membrane potential (\u0394\u03c8m) collapse, and cell death. These effects were associated with Erk signaling activation, upregulation of PGC-1\u03b1 genes expression and increased mitochondrial DNA. Our study underscores VEGF\u2019s multifaceted role in neuronal resilience beyond angiogenesis. Furthermore, these findings suggest that the VEGF\n                    <jats:sub>73-101<\/jats:sub>\n                    fragment may retain key neuroprotective and neurotrophic properties supporting further exploration of its therapeutic potential.\n                  <\/jats:p>","DOI":"10.1007\/s12035-025-05213-9","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T03:28:39Z","timestamp":1753932519000},"page":"16045-16060","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["VEGF and the VEGF73-101 Fragment Prevent MPP+ Induced Mitochondrial Dysfunction in a Cell Model of Parkinson\u2019s Disease"],"prefix":"10.1007","volume":"62","author":[{"given":"Stefania","family":"Zimbone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Battiato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Conti Nibali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Naletova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi Anna","family":"Pesce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"De Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Messina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Magr\u00ec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna Flora","family":"Tomasello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Grasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"5213_CR1","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/sj.jidsymp.5650016","volume":"11","author":"SA Eming","year":"2006","unstructured":"Eming SA, Krieg T (2006) Molecular mechanisms of VEGF-A action during tissue repair. 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