Melittin-induced modulation of mitochondrial physiology: Beyond the antitumoral actions

Melittin (MEL), a cationic amphipathic peptide derived from bee venom, exhibits dual roles in mitochondrial physiology, with both cytoprotective and cytotoxic outcomes. This review synthesizes current findings on MEL-induced modulation of mitochondrial pathways in normal and cancer cells. Beyond its well-documented roles in apoptosis regulation, MEL influences mitochondrial function by altering membrane potential, regulating respiratory chain activity, and impacting ATP production. These effects are context-dependent and vary across normal and tumor cell models. MEL can attenuate mitochondrial dysfunction by preserving mitochondrial membrane integrity and reducing reactive oxygen species, while in cancer cells, it often promotes mitochondrial depolarization, cytochrome c release, and caspase activation, culminating in intrinsic apoptotic signaling. Importantly, MEL modulates the expression of key proteins such as BAX, BCL-2, and APAF-1, and interacts with signaling cascades including PI3K/Akt, NF-κB, MAPKs, and Nrf2/HO-1. Recent studies have demonstrated that MEL also regulates mitochondrial quality control mechanisms, including the stimulation of mitophagy through PINK1/Parkin and AMPK-related pathways. Moreover, MEL interacts directly with mitochondrial membranes and affects enzymes critical for energy metabolism, such as F1-ATPase, contributing to altered bioenergetic output. These actions suggest that MEL's mitochondrial effects extend beyond cell death regulation, encompassing broader control over metabolic activity, oxidative stress, and organelle maintenance. Future investigations should integrate redox biology, bioenergetics, and mitochondrial signaling to optimize MEL's therapeutic applications. Altogether, MEL represents a unique modulator of mitochondrial health, whose dual actions necessitate rigorous contextual evaluation for clinical translation.