Cardiolipin-Specific Targeting of Melittin via Arg22 in Lipid Membranes: A Natural Toxin-Based Strategy for Treating Mitochondrial Dysfunction in Aging and Disease.
- 1Advanced STEM Research Center, Beijing Chaoyang Kaiwen Academy, Beijing 100018, China.
- 2Department of Pharmacology, University of Nevada Medical School, Reno, NV 89557, USA.
- 3Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia.
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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BibTeX
@article{abaza2026cardiolipinspecific,
title = {{Cardiolipin-Specific Targeting of Melittin via Arg22 in Lipid Membranes: A Natural Toxin-Based Strategy for Treating Mitochondrial Dysfunction in Aging and Disease.}},
author = {Safy M Sh M Abaza and Jiaqi Zhou and Ziqin Wang and Zanyu Pan and Haoran Ma and Yingdi Sun and Ruben K Dagda and Edward S Gasanoff},
journal = {Toxins},
year = {2026},
month = oct,
doi = {10.3390/toxins18100432},
url = {https://europepmc.org/article/MED/42931523},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cardiolipin-Specific Targeting of Melittin via Arg22 in Lipid Membranes: A Natural Toxin-Based Strategy for Treating Mitochondrial Dysfunction in Aging and Disease.
AU - Safy M Sh M Abaza
AU - Jiaqi Zhou
AU - Ziqin Wang
AU - Zanyu Pan
AU - Haoran Ma
AU - Yingdi Sun
AU - Ruben K Dagda
AU - Edward S Gasanoff
PY - 2026
DA - 2026/10/08
JO - Toxins
DO - 10.3390/toxins18100432
UR - https://europepmc.org/article/MED/42931523
AB - 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.
SN - 2072-6651
ER -