Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death

Abstract

Mitochondria are known to actively regulate cell death with the final phenotype of demise being determined by the metabolic and energetic status of the cell. Mitochondrial membrane permeabilization (MMP) is a critical event in cell death, as it regulates the degree of mitochondrial dysfunction and the release of intermembrane proteins that function in the activation and assembly of caspases. In addition to the crucial role of proapoptotic members of the Bcl-2 family, the lipid composition of the mitochondrial membranes is increasingly recognized to modulate MMP and hence cell death. The unphysiological accumulation of cholesterol in mitochondrial membranes regulates their physical properties, facilitating or impairing MMP during Bax and death ligand-induced cell death depending on the level of mitochondrial GSH (mGSH), which in turn regulates the oxidation status of cardiolipin. Cholesterol-mediated mGSH depletion stimulates TNF-induced reactive oxygen species and subsequent cardiolipin peroxidation, which destabilizes the lipid bilayer and potentiates Bax-induced membrane permeabilization. These data suggest that the balance of mitochondrial cholesterol to peroxidized cardiolipin regulates mitochondrial membrane properties and permeabilization, emerging as a rheostat in cell death.

Figure 1. Cholesterol regulates the cardiolipin/peroxidized cardiolipin status

A, under physiological settings the pool of mitochonrial cholesterol is low allowing unimpaired transport of GSH into the mitochondrial matrix by the 2-oxoglutarate (2-OG) carrier, with a minor role for the dicarboxylate carrier (DIC), at least in rat liver mitochondria. In this scenario, the generation of ROS by cell death stimuli such as TNF, hypoxia or Aβ, is controlled by GSH availability, ensuring the presence of intact cardiolipin in mitochondrial membranes. B, when the trafficking of cholesterol is stimulated as seen in different pathologies (e.g. ASH/NASH or Alzheimer's disease), the mitochondrial transport of GSH via 2-OG is impaired resulting in GSH depletion which stimulates the generation of ROS in response to TNF causing cardiolipin peroxidation (CLOOH), which destabilizes the lipid bilayer and contributes to MOM permeabilization (MOMP) mediated by Bax.

Figure 2. Paradoxical role of mitochondrial cholesterol in cell death

Since cholesterol regulates membrane dynamics and physical properties, the in situ enrichment in cholesterol impairs mitochondrial membrane permeabilization via MPT induced in response to atractyloside, which acts via adenine nucleotide translocator (ANT), Ca²⁺ or ROS, as well as the permeabilization of the outer membrane by active Bax. However, in pathological conditions associated with mitochondrial cholesterol trafficking and accumulation in both the inner and outer membranes via StAR expression potentiates mitochondrial membrane permeabilization in response to TNF/Fas, ROS, Bax or Aβ due to the mitochondrial GSH depletion. A role for the StAR family member MLN64 in the delivery of cholesterol to mitochondria remains to be fully established.