Cardiolipin-Specific Targeting of Melittin via Arg22 in Lipid Membranes: A Natural Toxin-Based Strategy for Treating Mitochondrial Dysfunction in Aging and Disease

The science

Original title

Cardiolipin-Specific Targeting of Melittin via Arg22 in Lipid Membranes: A Natural Toxin-Based Strategy for Treating Mitochondrial Dysfunction in Aging and Disease.

Authors

Abaza SMSM, Zhou J, Wang Z et al.

Journal

Toxins

Published

Oct 26, 2026

Study type

Study · in humans

PMID

42931523 ↗

DOI

10.3390/toxins18100432 ↗

Abstract

Bee venom melittin is a small protein with significant pharmacological potential. In this study, AutoDock simulations identified Arg22 as a key residue of melittin responsible for targeting the phosphate groups of cardiolipin (CL). Recombinant melittin with the native amino acid sequence, as well as a modified version with Arg22 substituted by Gly22, were cloned, expressed, and purified. The effects of both melittins on proton adsorption in CL-containing membranes, mitochondrial ATP production, and the formation of non-bilayer lipid structures were examined. Based on the array of computational and experimental data obtained in this work, together with published findings, we propose that Arg22, in tandem with Lys23, targets and neutralizes CL bound to conserved Lys7 and Lys43 of the ATP synthase rotor, thereby detaching CL from the rotor. These events promote a conical shape of CL, which triggers the formation of inverted micelles that entrap protons from the Fo subunit and transfer them to the proton pump of a respiratory complex. This study advances both the conceptual framework of mitochondrial energetics and the translational application of natural toxins. Specifically, the findings support the development of new pharmaceuticals aimed at counteracting the loss of mitochondrial energy production that occurs with aging and pathological conditions.

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