Cobra Venom Cytotoxins as a Tool for Probing Mechanisms of Mitochondrial Energetics and Understanding Mitochondrial Membrane Structure

• Published in: Toxins 2024-07, Vol.16 (7), p.287
• Main Authors: Gasanoff, Edward S, Dagda, Ruben K
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Amino acids; Animals; Apoptosis; ATP; ATP synthase; Bioenergetics; Cancer; Cells; Chemical synthesis; Chemiosmotic theory; cobra venom cytotoxins; Cytotoxicity; Cytotoxins; Cytotoxins - chemistry; Cytotoxins - pharmacology; Cytotoxins - toxicity; Dynamic structural analysis; Elapid Venoms - chemistry; Elapid Venoms - metabolism; Elapid Venoms - toxicity; Energy Metabolism - drug effects; Environmental factors; Humans; Hydrophobicity; Lipids; Membrane structure; Membrane structures; Membranes; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Molecular modelling; Molecular structure; neurodegeneration; non-bilayer lipid phase; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Phosphorylation; Plasma; Poisonous snakes; Proteins; Protons; Structure-function relationships; Therapeutic applications; updated working model of the chemiosmotic theory; Venom
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins16070287

In this paper, we provide an overview of mitochondrial bioenergetics and specific conditions that lead to the formation of non-bilayer structures in mitochondria. Secondly, we provide a brief overview on the structure/function of cytotoxins and how snake venom cytotoxins have contributed to increasing our understanding of ATP synthesis via oxidative phosphorylation in mitochondria, to reconcile some controversial aspects of the chemiosmotic theory. Specifically, we provide an emphasis on the biochemical contribution of delocalized and localized proton movement, involving direct transport of protons though the F unit of ATP synthase or via the hydrophobic environment at the center of the inner mitochondrial membrane (proton circuit) on oxidative phosphorylation, and how this influences the rate of ATP synthesis. Importantly, we provide new insights on the molecular mechanisms through which cobra venom cytotoxins affect mitochondrial ATP synthesis, mitochondrial structure, and dynamics. Finally, we provide a perspective for the use of cytotoxins as novel pharmacological tools to study membrane bioenergetics and mitochondrial biology, how they can be used in translational research, and their potential therapeutic applications.