Breaking down cardiolipin

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Sci. Signal.  29 Sep 2015:
Vol. 8, Issue 396, pp. ec279
DOI: 10.1126/scisignal.aad5234

Cardiolipin (CL) is a phospholipid that is important for energetic metabolism and is present in bacteria and the inner mitochondrial membrane of eukaryotes. Boynton and Shimkets found that Myxococcus xanthus CsgA and two of its eukaryotic homologs function as CL phospholipases. CsgA, a member of the short-chain alcohol dehydrogenase (SCAD) family of enzymes, is required for Myxococcus to form multicellular fruiting bodies in response to starvation. In vitro, purified recombinant CsgA oxidized the glycerol group of CL, yielding an unstable product that broke down into diacylglycerol (DAG), dihydroxyacetone, and orthophosphate. Experiments in which csgA mutants were supplemented with fractions of Myxococcus lipid extracts suggested that this DAG species was further modified into a species of triacylgylcerol (TAG). TAGs are the main constituent of the lipid bodes that are formed during sporulation but absent from csgA mutants, implying that the catabolism of CL is important for sporulation. Two other SCADs, Drosophila melanogaster Sniffer and human HSD10, also catalyzed the oxidation of CL in vitro. Both Sniffer and HSD10 are important for proper mitochondrial function and protect neurons from degeneration. Mutant forms of HSD10 associated with mitochondrial disease failed to oxidize CL in vitro. Peroxidation of CL, such as that which may occur during oxidative stress, triggers apoptosis. In vitro, HSD10 preferentially oxidized species of CL containing oxidized fatty acid groups (CLox) compared with species of CL containing nonoxidized fatty acids. The peptide β-amyloid (Aβ), a major component of the amyloid plaques associated with Alzheimer's disease, binds to and inhibits HSD10. The presence of Aβ inhibited the enzymatic activity of HSD10 toward CLox in vitro. The authors propose that HSD10 is neuroprotective because it degrades CL that has been damaged by reactive oxygen species, thereby preventing apoptosis. One of the ways in which Aβ may contribute to neurodegeneration is by preventing HSD10 from removing oxidized CL.

T. O. Boynton, L. J. Shimkets, Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin phospholipases. Genes Dev. 29, 1903–1914 (2015). [PubMed]