Dual-targeted Mitophagy activation by curcumin-Zn co-delivery mediates neuroprotection in zebrafish through...

Neurodegenerative diseases are currently incurable, but emerging research highlights mitochondrial homeostasis as a key therapeutic target. Concurrently, exploring bioactive compounds from food sources offers a long-term strategy for prevention and adjuvant therapy. Previously, a green and soy protein isolate (SPI)-based curcumin‑zinc ternary nanocomplex was newly developed and shown to exhibit potent in vitro antioxidant and neuroprotective activity. As a continuous study, the present work further investigated the neuroprotective efficiency of complex from the perspective of mitochondrial function modulation, employing both cellular and animal models (zebrafish model of Parkinson's disease (PD)). Crucially, the ternary complex significantly promoted mitophagy, a key mitochondrial quality control process, in HEK-293 T-mtKeima reporter cells. Behavioral, histological, and biochemical analyses demonstrated that, as compared to the PD zebrafish model, the nanocomplex treatment significantly preserved cerebrovascular integrity (increasing vascular density by 71.8%), elevated cerebral mitochondrial density (by 83.9%), and restored locomotor function (improving swimming distance and speed by 1.51- and 1.53-fold, respectively). Mechanistically, the complex attenuated oxidative damage while activating mitophagy through dual modulation of the PINK1/Parkin and PI3K/AKT/mTOR signaling axes, thereby restoring mitochondrial dynamics. These findings highlight the SPI-curcumin‑zinc nanocomplex as a multifaceted neuroprotective agent with translational potential for neurodegenerative disorders.