Cardiolipin is a mitochondrial phospholipid with a characteristic acyl chain composition that depends on the function of tafazzin, a phospholipid-lysophospholipid transacylase, although the enzyme itself lacks acyl specificity. We incubated isolated tafazzin with various mixtures of phospholipids and lysophospholipids, characterized the lipid phase by 31P-NMR and measured newly formed molecular species by MS. Substantial transacylation was observed only in nonbilayer lipid aggregates, and the substrate specificity was highly sensitive to the lipid phase. In particular, tetralinoleoyl-cardiolipin, a prototype molecular species, formed only under conditions that favor the inverted hexagonal phase. In isolated mitochondria, <1% of lipids participated in transacylations, suggesting that the action of tafazzin was limited to privileged lipid domains. We propose that tafazzin reacts with non–bilayer-type lipid domains that occur in curved or hemifused membrane zones and that acyl specificity is driven by the packing properties of these domains.
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We are grateful to B. De Kruijff for stimulating discussions. This work was supported by the Barth Syndrome Foundation, by the National Institutes of Health (HL078788 to M.S., HL091154 to M.R., 1U54GM094598 to D.L.S.) and by the Canadian Natural Sciences and Engineering Research Council (9848 to R.M.E.).
The authors declare no competing financial interests.
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Schlame, M., Acehan, D., Berno, B. et al. The physical state of lipid substrates provides transacylation specificity for tafazzin. Nat Chem Biol 8, 862–869 (2012). https://doi.org/10.1038/nchembio.1064
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