Loss of protein association causes cardiolipin degradation in Barth syndrome

• Published in: Nature chemical biology Vol. 12; no. 8; pp. 641 - 647
• Main Authors: Xu, Yang, Phoon, Colin K L, Berno, Bob, D'Souza, Kenneth, Hoedt, Esthelle, Zhang, Guoan, Neubert, Thomas A, Epand, Richard M, Ren, Mindong, Schlame, Michael
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2016
• Subjects: 101/58; 13; 631/92/1643; 631/92/287/1192; 64/24; 64/60; 692/699/75; Barth Syndrome - metabolism; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cardiolipins - metabolism; Cell Biology; Chemistry; Chemistry/Food Science; Humans
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.2113

Monolyso-cardiolipin (MLCL) accumulates in individuals with Barth syndrome, but this can be mitigated by stabilization of cardiolipin from metabolism to MLCL via assembly into supercomplexes of oxidative phosphorylation proteins. This process was found to be defective in subjects with Barth syndrome. Cardiolipin is a specific mitochondrial phospholipid that has a high affinity for proteins and that stabilizes the assembly of supercomplexes involved in oxidative phosphorylation. We found that sequestration of cardiolipin in protein complexes is critical to protect it from degradation. The turnover of cardiolipin is slower by almost an order of magnitude than the turnover of other phospholipids. However, in subjects with Barth syndrome, cardiolipin is rapidly degraded via the intermediate monolyso-cardiolipin. Treatments that induce supercomplex assembly decrease the turnover of cardiolipin and the concentration of monolyso-cardiolipin, whereas dissociation of supercomplexes has the opposite effect. Our data suggest that cardiolipin is uniquely protected from normal lipid turnover by its association with proteins, but this association is compromised in subjects with Barth syndrome, leading cardiolipin to become unstable, which in turn causes the accumulation of monolyso-cardiolipin.