Ren Mindong, Chen Shiyu, Greenberg Miriam L, Schlame Michael
Department of Anesthesiology, New York University Grossman School of Medicine, New York, New York, USA.
Department of Anesthesiology, New York University Grossman School of Medicine, New York, New York, USA.
J Biol Chem. 2025 May 14;301(6):110237. doi: 10.1016/j.jbc.2025.110237.
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 monolysocardiolipin (MLCL). While taz1 homologs have been identified in all eukaryotes, cld1 homologs have remained obscure. Here, we demonstrate that α/β-hydrolase domain 18 (ABHD18), a highly conserved protein of plants, animals, and humans, is functionally homologous to Cld1. Knockdown of Abhd18 decreased the concentration of MLCL in murine, Taz-knockout myoblasts. Inactivation of Abhd18 in Drosophila substantially increased the abundance of CL. Abhd18 inactivation also reversed the increase in the rate of CL degradation, as measured with C isotopes, and the accumulation of deacylated CLs, such as MLCL and dilyso-CL, in tafazzin (TAZ)-deficient flies. CL species with more than five 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.
心磷脂（CL）是线粒体的标志性磷脂，带有四条在从头合成后会被重塑的脂肪酸链。在酵母中，重塑过程是由Cld1（一种从CL上移除脂肪酸的脂肪酶）和Taz1（一种将脂肪酸从另一种磷脂转移至单溶血心磷脂（MLCL）的转酰基酶）共同作用完成的。虽然在所有真核生物中都已鉴定出taz1同源物，但cld1同源物一直不为人所知。在此，我们证明，α/β水解酶结构域18（ABHD18），一种在植物、动物和人类中高度保守的蛋白质，在功能上与Cld1同源。敲低Abhd18会降低小鼠Taz基因敲除成肌细胞中MLCL的浓度。在果蝇中使Abhd18失活会大幅增加CL的丰度。Abhd18失活还逆转了用碳同位素测量的CL降解速率的增加，以及tafazzin（TAZ）缺陷果蝇中脱酰基CL（如MLCL和二溶血心磷脂）的积累。具有超过五个双键的CL种类对ABHD18有抗性。我们的数据表明，ABHD18就是在小鼠和果蝇以及大概在其他生物体中水解CL的难以捉摸的脂肪酶。我们发现，ABHD18不是只去除一条脂肪酸链，而是会进一步使CL脱酰基。因此，ABHD18催化CL的分解，而TAZ保护CL不被降解。
