Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins.

Monolysocardiolipin (MLCL) is a three-tailed variant of cardiolipin (CL), the signature lipid of mitochondria. MLCL is not normally found in healthy tissue but accumulates in mitochondria of people with Barth syndrome (BTHS), with an overall increase in the MLCL:CL ratio. The reason for MLCL accumulation remains to be fully understood. The effect of MLCL build-up and decreased CL content in causing the characteristics of BTHS are also unclear. In both cases, an understanding of the nature of MLCL interaction with mitochondrial proteins will be key. Recent work has shown that MLCL associates less tightly than CL with proteins in the mitochondrial inner membrane, suggesting that MLCL accumulation is a result of CL degradation, and that the lack of MLCL-protein interactions compromises the stability of the protein-dense mitochondrial inner membrane, leading to a decrease in optimal respiration. There is some data on MLCL-protein interactions for proteins involved in the respiratory chain and in apoptosis, but there remains much to be understood regarding the nature of MLCL-protein interactions. Recent developments in structural, analytical and computational approaches mean that these investigations are now possible. Such an understanding will be key to further insights into how MLCL accumulation impacts mitochondrial membranes. In turn, these insights will help to support the development of therapies for people with BTHS and give a broader understanding of other diseases involving defective CL content.