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.
Highlights
There are still many details remain enigmatic in molecular mechanisms concerning the role of cardiolipin in supporting the activities of the electron transport chain (ETC) and the ATP synthesis, it becomes increasingly clear that cardiolipin is an indispensable molecule in the ETC and ATP synthesis of inner mitochondrial membrane (IMM), which is required for proper physiological structure and functioning of mitochondria
Several other cases of mitochondrial dysfunction associated with the decreased levels of cardiolipin in the IMM that trigger abnormalities in the respiratory chain, decline in ATP synthesis, and loss in the structural integrity of mitochondria, leading to the cardiovascular disease pathogenesis, are caused by the genetic disorders, such as Senders syndrome and dilated cardiomyopathy with ataxia, both of which inhibit cardiolipin biosynthesis [55,56]
Extensive studies of the SS peptides’ actions on mitochondrial activities and their related physiological effects in cells, tissues, and bodies revealed that SS peptides can induce a broad range of physiological and pharmacological reactions, including rejuvenation of oxidative phosphorylation and decreasing the reactive oxygen species production, inhibition of cardiolipin peroxidation, remodeling of mitochondrial cristae structure in aged mice, upregulation of enzymes required for cardiolipin biosynthesis and remodeling, restoration of mitochondrial bioenergetics and dynamics, restoration of cellular structure and function during aging, prevention of cell death and inflammation, and boosting body’s natural ability to heal itself [1]
Summary
In cells of tissues with a high energy demand, such as heart muscles and skeletal musculature, there is an increased number of large and elongated mitochondria with numerous and tightly stacked cristae membranes, which take up most of the mitochondrial volume [1]. A decrease in overall surface area of cristae results in the decreased activity of the respiratory protein complexes, especially CI and CIV [8,9,10], which accounts for the decreased production of ATP [11] It has been observed in the elderly and in patients with cardiovascular and other diseases that decline in ATP production impairs pathways of programmed cell death [12], resulting in an increased rate of morbidity and mortality
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