PA1b-like peptides alleviate mitochondrial dysfunction induced by glucose toxicity through interaction with VDAC1 in β-cells

Abstract

PA1b-like peptides, which are extracted from the seeds of members of the Fabaceae family, display remarkable hypoglycemic and β-cell-protective activities when administered orally. However, the direct targets and mechanisms of action of these peptides in islet β-cells remain unclear. In this study, we found that PA1b-like peptides were mainly distributed in the cotyledon of soybean, rather than in the germ and seed coat. We also identified a direct interaction between PA1b-like peptides and voltage-dependent anion channels (VDACs), with binding energies less than −7 kcal mol⁻¹. Molecular dynamics simulations demonstrated that hydrogen bonding, hydrophobic interactions, and van der Waals forces assist these peptides in forming stable and tight complexes with VDAC1. Moreover, as a member of the PA1B-like peptide family, vglycin (VG) protected mitochondrial function by maintaining the ROS level, ATP production, mitochondrial membrane potential (ΔΨ_m), intracellular Ca²⁺ inflow and insulin secretion in β-cells under high glucose stimulation. All these effects were reliant on the direct interaction between VG and VDAC1 in β-cells. This study provides a new strategy for the restoration of mitochondrial function in β-cells under glucose toxicity and establishes a theoretical basis for the treatment of type 2 diabetes (T2D) by PA1b-like peptides.