Prohibitin 2 mediates the mitochondrial protective effect of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr.

Certain dairy products have been reported to reduce the risk of cognitive decline in older adults and patients with Alzheimer's disease (AD). Intake of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr (GTWY) improves mild cognitive impairment in healthy adults, while GTWY administration in mice suppresses AD-like pathologies, including amyloid-beta (Aβ) accumulation and neuroinflammation. GTWY treatment also reduces Aβ-induced mitochondrial dysfunction in neuronal cells. However, the molecular mechanisms underlying these effects remain unclear. Here, we identified prohibitin 2 (PHB2) as a direct binding partner of GTWY in human neuroblastoma SH-SY5Y cells and investigated its role in the mitochondrial protective effect of GTWY. GTWY treatment increased the abundance of the prohibitin complex detected by blue native PAGE without affecting PHB1 or PHB2 expression. Moreover, PHB2 knockdown abolished the mitochondrial protective effect of GTWY, indicating that PHB2 mediates this effect. These findings suggest that GTWY binding to PHB2 modulates the functional state of the prohibitin complex, thereby preserving mitochondrial function. Our results provide new insights into the molecular mechanisms underlying the mitochondrial protective effects of whey-derived peptides and highlight the potential role of the prohibitin complex in mediating these effects.