Intranasal Administration of an Arginine-Enriched Penetratin Peptide Confers Neuroprotection via Mitochondrial Functional Modulation in a Genetic Parkinson's Disease Model.

BACKGROUND: Mitochondrial dysfunction is a central pathogenic mechanism in Parkinson's disease (PD), particularly in genetic forms associated with respiratory chain impairment. Disease-modifying therapies capable of restoring neuronal bioenergetics while achieving non-invasive brain delivery remain lacking. This study investigated the therapeutic potential of an arginine-enriched penetratin-derived peptide (PenArg) in a genetic PD model carrying the UQCRC1 (p.Tyr314Ser) mutation. METHODS: The effects of PenArg labeled with 5-FAM- or biotin were evaluated in UQCRC1 knock-in SH-SY5Y cells and mice. Mitochondrial function, neuronal survival, and apoptosis were assessed using biochemical and imaging analyses. Brain distribution was evaluated 2 h after intranasal administration, and therapeutic efficacy was examined following chronic intranasal treatment (three times weekly for six months). RESULTS: PenArg restored mitochondrial membrane potential, improved neuronal viability, and reduced oxidative stress-induced apoptosis in cellular models. Imaging studies demonstrated partial mitochondrial localization in vitro and in vivo. Intranasal administration significantly improved locomotor performance, preserved dopaminergic neurons in the substantia nigra (SN) and striatum, and maintained hippocampal neuronal structure. Brain distribution analysis confirmed widespread brain penetration after intranasal administration. PenArg restored ATP synthase subunit beta expression and complex III activity while reducing cytochrome c release and caspase-3 activation in SN neurons. Treatment additionally attenuated skeletal muscle atrophy, enhanced antioxidant responses, and reduced circulating pro-inflammatory cytokines. CONCLUSION: PenArg confers neuroprotection through functional modulation of mitochondrial homeostasis and produces multisystem therapeutic benefits. Intranasal administration represents a non-invasive strategy with disease-modifying potential for mitochondrial-related neurodegenerative disorders.