Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease

Abstract

Apitherapy has a long history in treating Parkinson's disease (PD) in humans, with evidence suggesting that bee venom (BV) can mitigate Parkinson's symptoms. Central to BV's effects is melittin (MLT), a principal peptide whose neuroprotective mechanisms in PD are not fully understood. The study investigated the effects of MLT on an experimental PD model in mice and dopaminergic neuron cells, induced by MPTP or MPP⁺. We concentrate on the autophagic response elicited by MLT during PD pathogenesis. The findings showed that MLT was shown to protect against MPP⁺/MPTP cytotoxicity and preserve tyrosine hydroxylase (TH) levels, indicating neuronal safeguarding. Remarkably, MLT instigated mitophagy, enhancing mitochondrial homeostasis in MPP⁺-exposed SH-SY5Y cells. Further, MLT's promotion of mitophagy was confirmed to be AMPK/mTOR signaling-dependent. Validation using Bafilomycin A₁, an autophagy inhibitor, confirmed MLT's neuroprotective role, with autophagy inhibition negating MLT's benefits and reducing TH preservation. These findings illuminate MLT's therapeutic potential, particularly its modulation of mitochondrial dysfunction in PD pathology. Our research advances the understanding of MLT's mechanistic action, emphasizing its role in mitochondrial autophagy and AMPK/mTOR signaling, offering a novel perspective beyond the symptomatic relief associated with BV.

Keywords: AMPK/mTOR signaling pathway; Dopaminergic neuron; Melittin; Mitophagy; Parkinson's disease.