VDAC1-Targeted NHK1 Peptide Recovers Mitochondrial Dysfunction Counteracting Amyloid-β Oligomers Toxicity in Alzheimer's Disease

Mitochondrial dysfunction has been implicated in a broad range of age-related pathologies and has been proposed as a causative factor in Alzheimer's disease (AD). Analysis of post-mortem brains from AD patients showed increased levels of Voltage-dependent anion-selective channel 1 (VDAC1) in the dystrophic neurites surrounding amyloid-beta (A beta) deposits, suggesting a direct association between VDAC1 and mitochondrial toxicity. VDAC1 is the most abundant pore-forming protein of the outer mitochondrial membrane and, as a channel, it plays a pivotal role in regulating cellular bioenergetics, allowing the continuous exchange of ions and metabolites (ATP/ADP, Krebs cycle intermediates) between cytosol and mitochondria. In light of this evidence, we looked into the effects of A beta oligomers on VDAC1 functions through electrophysiological and respirometric techniques. Our findings indicate that A beta oligomers significantly modify the conductance, voltage dependency, and kinetic features of VDAC1, as well as its slight selectivity for anions, leading to a marked preference for cations. Given that VDAC1 is mainly involved in the trafficking of charged molecules in and out of mitochondria, a general reduction of cell viability and mitochondrial respiration was detected in neuroblastoma cells and primary cortical neurons exposed to A beta oligomers. Interestingly, the toxic effect mediated by A beta oligomers was counteracted by the use of NHK1, a small synthetic, cell-penetrating peptide that binds and modulates VDAC1. On these results, VDAC1 emerges as a crucial molecule in mitochondrial dysfunction in AD and as a promising pharmacological target for the development of new therapeutic avenues for this devastating neurodegenerative disease still without a cure.