ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids
Mindong Ren, Shiyu Chen, Miriam L. Greenberg, Michael Schlame
Abstract
<h2>ABSTRACT</h2> Cardiolipin (CL), the signature phospholipid of mitochondria, carries four fatty acids that are remodeled after de novo synthesis. In yeast, remodeling is accomplished by the joint action of Cld1, a lipase that removes a fatty acid from CL, and Taz1, a transacylase that transfers a fatty acid from another phospholipid to monolyso-CL. While <i>taz1</i> homologues have been identified in all eukaryotes, <i>cld1</i> homologues have remained obscure. Here we demonstrate that ABHD18, a highly conserved protein of plants, animals, and humans, is functionally homologous to Cld1. Knockdown of <i>Abhd18</i> decreased the concentration of monolyso-CL in murine, <i>Taz</i>-knockout myoblasts. Inactivation of <i>Abhd18</i> in Drosophila substantially increased the abundance of CL. <i>Abhd18</i> inactivation also reversed the increase in the rate of CL degradation, as measured with <sup>13</sup>C isotopes, and the accumulation of deacylated CLs, such as monolyso-CL and dilyso-CL, in TAZ-deficient flies. CL species with more than 5 double bonds were resistant to ABHD18. Our data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL in mice and flies and presumably in other organisms. Rather than removing just one fatty acid, we show that ABHD18 deacylates CL further. Thus, ABHD18 catalyzes the breakdown of CL whereas TAZ protects CL from degradation.