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Loss of protein association causes cardiolipin degradation in 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.

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Figure 1: Acyl turnover of CL is increased in lymphoblasts from subjects with BTHS.
Figure 2: Tafazzin deficiency increases the glycerol turnover of CL in Drosophila and mammalian cells.
Figure 3: MLCL is present in intact mitochondria with normal protein turnover.
Figure 4: CL, but not MLCL, is associated with proteins.
Figure 5: Supercomplexes protect CL from degradation.
Figure 6: Unsaturated fatty acids stabilize CL.


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This research was supported in part by the National Institutes of Health (grant 1R01GM115593 to M.S., Shared Instrumentation Grant RR027990 to T.A.N., and NINDS core center grant NS050276 to T.A.N.). Funds were also provided by the Barth Syndrome Foundation (to C.K.L.P. and R.M.E.). Mouse embryonic stem cells with and without tafazzin knockout were obtained from Z. Khuchua (Cincinnati Children's Hospital, Cincinnati, Ohio, USA).

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Y.X., C.K.L.P., M.R., and M.S. performed experiments and analyzed data. B.B., K.D., R.M.E., and M.S. designed and performed the NMR experiments. E.H., G.Z., and T.A.N. designed and performed the proteomics analyses. M.S. supervised the entire study and wrote the paper. C.K.L.P., T.A.N., M.R., and R.M.E. revised the manuscript.

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Correspondence to Michael Schlame.

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The authors declare no competing financial interests.

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Xu, Y., Phoon, C., Berno, B. et al. Loss of protein association causes cardiolipin degradation in Barth syndrome. Nat Chem Biol 12, 641–647 (2016).

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