Tafazzin deficiency causes substantial remodeling in the lipidome of a mouse model of Barth Syndrome cardiomyopathy.

Hachmann M, Gülcan G, Rajendran R, Höring M, Liebisch G, Bachhuka A, Kohlhaas M, Maack C, Ergün S, Dudek J, and Karnati S. (2024) Tafazzin deficiency causes substantial remodeling in the lipidome of a mouse model of Barth Syndrome cardiomyopathy. Frontiers in Molecular Medicine

Barth Syndrome (BTHS) is a rare disease with a prevalence of less than 1 in 300 000 and is caused by a recessive mutation in the phospholipid acyltransferase tafazzin gene on the X chromosome. This gene is responsible for catalyzing the final step in remodeling cardiolipin, which is a glycerophospholipid found in the inner mitochondrial membrane. A mutation in tafazzin (TAZ) results in an inability for mature cardiolipin to be produced and consequently an increase in levels of the intermediate cardiolipin types. This ratio of mature cardiolipin to intermediate cardiolipin, such as monolysocardiolipin (MLCL), can be used to diagnose BTHS. The composition of the mitochondrial membrane influences the function of the organelle therefore correct synthesis of its components, such as cardiolipin, is crucial. The morphology of cardiolipin gives it an important role in the structure of mitochondria and causes membrane bends due to its wedge-shape. These bends are essential in the formation of lamellar crista and allows fission and fusion, and cardiolipin also influences the function of mitochondrial membrane proteins. As the heart has one of the largest energy demands of all the organs in the human body, it relies highly on mitochondria to provide its primary source of energy. Unsurprisingly, BTHS is characterized by muscle weakness and specifically a weakened enlarged heart. A deficiency of tafazzin has also been associated with fluctuations to other lipid species including plasmalogens but these changes are not well understood. Hachmann et al were interested in determining the lipid alterations that occur in BTHS and how this affects the pathology of the disease.

To perform this work, a BTHS mouse model where tafazzin was systemically reduced through expression of an interfering shRNA (TAZ-KD) was used to facilitate the breakdown of TAZ mRNA and were compared against wild-type (WT) mice. This is the most used animal model for studying BTHS as it closely matches the human pathology. Hearts from 10-week-old and 50-week-old mice were collected and electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to determine the distribution of lipid species within the organ. During this analysis, the authors identified 193 different species in the heart with triglycerides consisting of 50 of them. The TAZ deficiency resulted in differences in phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), choline plasmalogens (PC-O), and ethanolamine plasmalogens (PE-P). Of the PCs, 22 were analyzed and 8 showed a significant difference in concentration between the two genotypes at at least one of the two timepoints. PC 34:2, PC 36:2 and PC 38:4 were higher at both timepoints in the TAZ-KD group, while PC 38:6, PC 40:6, and PC 40:7 were higher in the WT group at both timepoints. For the PEs, 15 species were analyzed and only 1 did not have a significant difference between the genotypes. Of these, PE 34:2, PE 36:2, PE 36:3, PE 36:4, PE 38:3, PE 38:4, PE 38:5, and PE 40:4 were all significantly higher in the TAZ-KD group at both timepoints. When analyzing the 6 choline plasmalogen species that were identified, PC-O 34:2, PC-O 38:6, and PC-O 38:7 were reduced in the TAZ-KD groups at both timepoints, while PC-O 36:5 was greater in the TAZ-KD group. PC-O 36:5 was also one of the few lipid species that differed within the same genotype between the two timepoints, with the 10-week-old mice having higher levels than the 50-week-olds. When looking at the PE-Ps, 12 species were significantly different between the two genotypes. Of these, PE-P 16:0/20:4, PE-P 18:0/20:4, and PE-P 18:1/20:4 were significantly higher in TAZ-KD animals at both timepoints. Interestingly, PE-P levels were significantly reduced in 50-week-old WT mice compared to 10-week-old mice. Also, PE-P species with docosahexaenoic acid (DHA) were the most abundant ethanolamine plasmalogen species in the heart and these species showed no significant changes.

Hachmann et al were interested in determining the effect that knocking down tafazzin, responsible for remodeling cardiolipin, would have on the concentration of lipid species. Wild-type mice were compared against a standard mouse model of Barth Syndrome and lipid levels were determined in 10-week-old and 50-week-old mice, the latter of which were expected to have developed heart failure. The authors demonstrated statistically significant changes to the lipidome in the tafazzin-deficient mice at both timepoints and many of the trends seen were consistent across both. Interestingly, ethanolamine plasmalogen levels were found to be higher in the BTHS model compared to the wild-type animal. It is suggested that this may have occurred as a response to protect other phospholipids and lipids against degradation and damage since the vinyl-ether bond can scavenge radical oxygen species, which have been stated to be increased in other BTHS literature. Future work should look at these alterations in lipids as possible treatment targets for Barth Syndrome.