Cardiolipin, Non-Bilayer Structures and Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

Abstract

The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto–Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.

Bee Venom Melittin Disintegrates the Respiration of Mitochondria in Healthy Cells and Lymphoblasts, and Induces the Formation of Non-Bilayer Structures in Model Inner Mitochondrial Membranes

“…Regarding the model of IMM, we prepared oriented multibilayer films made of 80 mol% PC and 20 mol% CL, which also proved to be suitable for the accurate calculation of 5-DSA EPR parameters. This lipid film allowed us to model the interaction of melittin with CL, a signature phospholipid of mitochondria and a key phospholipid in regulating bioenergetics in the IMM [2].…”

“…This finding allows us to suggest that melittin at very low concentrations may act in an opposite way to melittin action at higher concentrations. We suggest that melittin at very low concentrations may act similarly to the CL-targeting SS-tetrapeptides that rejuvenate mitochondrial functions and remodel mitochondrial membranes, leading to tissue regeneration during aging and pathophysiological conditions [1,2].…”

“…Membrane-active peptides of cationic nature, such as synthetic Szeto-Schiller tetrapeptides and cobra venom polypeptides, have been successfully used in probing the molecular mechanisms of mitochondrial bioenergetics in states of health and dysfunction [1,2]. Molecular details of cardiolipin-targeting by Szeto-Schiller tetrapeptides that trigger a variety of physiological reactions, leading to the rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria, are being extensively investigated [1].…”

“…Molecular details of cardiolipin-targeting by Szeto-Schiller tetrapeptides that trigger a variety of physiological reactions, leading to the rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria, are being extensively investigated [1]. Application of cobra venom polypeptides in probing the structure-function mechanisms of mitochondrial membranes led to new understandings about the role of non-bilayer lipid structures in mitochondrial bioenergetics [2].…”

“…Due to the electrostatic attraction of melittin to acidic phosphatidylserine (PS), which has been shown in our recent study in lipid dispersions and unilamellar liposomes [20], it has been suggested that melittin may interact with membranes of cancer cells with greater avidity than with membranes of healthy cells [20]. Although we have recently examined the molecular binding of melittin to the PS-containing membrane in model lipid systems [20], the interaction of melittin with membranes containing other acidic phospholipids such as phosphatidic acid (PA), another phospholipid found on the outer leaflet of cancer cells [21,22], and cardiolipin (CL), a signature phospholipid of IMM [2], have not yet been investigated. Molecular mechanisms leading to melittin-induced disintegration of PS, PA, or CL-containing membranes have never been studied before.…”