Cardiolipin Oxidation in Mitochondrial Dysfunction
An interesting question is posed here by some of the researchers responsible for creating plastoquinone mitochondrially-targeted antioxidants. To what degree do mitochondrially-targeted antioxidants improve mitochondrial function and modestly slow aging by preventing cardiolipin oxidation? Past a certain level of detail, less is known of mitochondrial biochemistry than one might think. This organelle is very well studied, but it is still the case that many approaches known to improve mitochondrial function are incompletely understood, or only understood in outline. It is clear that the mitochondrial generation of reactive oxygen species is a problem that increases alongside mitochondrial dysfunction with age, but down in the depths of the interaction of many different molecules there is room for argument and opinion regarding how it all actually works in practice.
Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function (6), which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation.
Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging.