VEGF and the VEGF73-101 Fragment Prevent MPP+ Induced Mitochondrial Dysfunction in a Cell Model of Parkinson's Disease

: Vascular endothelial growth factor (VEGF) is best known for its role in angiogenesis, but emerging evidence suggests neurotrophic and neuroprotective functions most likely connected to energy homeostasis pathways. 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's disease (PD). To investigate the VEGF relevance in PD, we exposed differentiated SH-SY5Y cells to MPP+, a toxin inducing a PD-like phenotype. Both VEGF and a mimic peptide (VEGF73-101) reduced MPP+-induced uncoupled respiration, mitochondrial membrane potential (Δψm) collapse, and cell death. These effects were associated with Erk signaling activation, upregulation of PGC-1α genes expression and increased mitochondrial DNA. Our study underscores VEGF's multifaceted role in neuronal resilience beyond angiogenesis. Furthermore, these findings suggest that the VEGF73-101 fragment may retain key neuroprotective and neurotrophic properties supporting further exploration of its therapeutic potential.