Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins

Abstract

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.

A mouse model of short‐term, diet‐induced fatty liver with abnormal cardiolipin remodeling via downregulated Tafazzin gene expression

“…Once they are identified, this issue may be resolved. Second, we attributed abnormal CL remodeling to mitochondrial dysfunction as previously mentioned 4–6, 12, 24, 25, 27, 34 . Therefore, in our future studies, we will focus on hepatic mitochondrial function directly to further elucidate the phenotype.…”

“…This regular remodeling plays an important role in maintaining mitochondrial function 24 . In another study, an increase in MLCL level caused by abnormal CL remodeling was attributed to mitochondrial dysfunction 25 . Monolysocardiolipin does not strongly interact with mitochondrial membrane proteins 26 but causes an inadequate production of electron transport chain‐mediated ATP 27 .…”

Altered Cardiolipin Metabolism is Associated with Cardiac Mitochondrial Dysfunction in Pulmonary Vascular Remodeled Perinatal Rat Pups

“…1B). LysoCL accumulation is known to cause mitochondrial bioenergetic dysfunction (24). We observed elevated trilinoleoyl-lysoCL (L3-lysoCL) species in hearts (which was not certified by peer review) is the author/funder.…”

Absence of cardiolipin from the outer leaflet of a mitochondrial inner membrane mimic restricts Opa1-mediated fusion

“…MLCL accumulation occurs in Barth syndrome (Valianpour et al, 2005). The three-acyl chain structure of MLCL (and its degradation products) are predicted to generate a "flatter" bilayer, less susceptible to curvature (Duncan, 2020). Cristae models indicate bilayers with high CL prefer highly curved regions and are prone to "defects" due to exposed hydrophobic regions.…”