Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1) is the most abundant isoform of the outer mitochondrial membrane (OMM) porins and the principal gate for ions and metabolites to and from the organelle. VDAC1 is also involved in a number of additional functions, such as the regulation of apoptosis. Although the protein is not directly involved in mitochondrial respiration, its deletion in yeast triggers a complete rewiring of the whole cell metabolism, with the inactivation of the main mitochondrial functions. In this work, we analyzed in detail the impact of VDAC1 knockout on mitochondrial respiration in the near-haploid human cell line HAP1. Results indicate that, despite the presence of other VDAC isoforms in the cell, the inactivation of VDAC1 correlates with a dramatic impairment in oxygen consumption and a re-organization of the relative contributions of the electron transport chain (ETC) enzymes. Precisely, in VDAC1 knockout HAP1 cells, the complex I-linked respiration (N-pathway) is increased by drawing resources from respiratory reserves. Overall, the data reported here strengthen the key role of VDAC1 as a general regulator of mitochondrial metabolism.

Male infertility affects nearly 50% of infertile couples, with various underlying causes, including endocrine disorders, testicular defects, and environmental factors. Spermatozoa rely on mitochondrial oxidative metabolism for motility and fertilization, with mitochondria playing a crucial role in sperm energy production, calcium regulation, and redox balance. Voltage-dependent anion channels (VDACs), located on the outer mitochondrial membrane, regulate energy and metabolite exchange, which are essential for sperm function. This review offers an updated analysis of VDACs in the male reproductive system, summarizing recent advances in understanding their expression patterns, molecular functions, and regulatory mechanisms. Although VDACs have been widely studied in other tissues, their specific roles in male reproductive physiology still remain underexplored. Special attention is given to the involvement of VDAC2/3 isoforms, which may influence mitochondrial function in sperm cells and could be implicated in male fertility disorders. This update provides a comprehensive framework for future research in reproductive biology, underscoring the significance of VDACs as a molecular link between mitochondrial function and male fertility.

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 (VEGF _73-101 ) 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 VEGF _73-101 fragment may retain key neuroprotective and neurotrophic properties supporting further exploration of its therapeutic potential.