加拿大多伦多大学Jason Moffat课题组近日取得一项新成果。经过不懈努力，他们的最新研究提出了基因抑制使ABHD18成为Barth综合征的治疗靶点。相关论文于2025年9月3日发表在《自然》杂志上。

该课题组研究人员将ABHD18描述为CL生物合成途径中的候选去乙酰化酶。因此，ABHD18在体外将CL转化为单聚心磷脂（MLCL），其在细胞和小鼠中的失活导致血清和组织中向nCL转变。值得注意的是，ABHD18失活可以挽救细胞中的线粒体缺陷以及与Barth综合征相关的小鼠的发病率和死亡率。这种罕见的遗传性疾病的特点是由于TAFAZZIN （TAZ）失活突变导致MLCL的积累，TAZ编码CL重塑级联反应中的最后一种酶。该研究团队还发现了一种选择性的、共价的、小分子的ABHD18抑制剂，可以拯救人类患者和鱼胚胎成纤维细胞中的TAZ突变表型。这项研究强调了一个单基因疾病基因抑制的显著例子，揭示了CL生物合成途径中的典型酶。

据介绍，心磷脂（Cardiolipin， CL）是线粒体内膜的标志性磷脂，在那里它稳定电子传递链蛋白复合物。CL生物合成的最后一步涉及到它的重塑：新生酰基链与更长的不饱和链交换。然而，负责切割新生CL（nCL）的酶仍然存在。

附：英文原文

Title: Genetic suppression features ABHD18 as a Barth syndrome therapeutic target

Author: Masud, Sanna N., Srivastava, Anchal, Mero, Patricia, Echezarreta, Victoria Saba, Anderson, Eve, van Buren, Lennard, Wei, Jiarun, Taylor, David Thomson, Farias, Adrian Granda, Mikolajewicz, Nicholas, Shaw, Angela, Murareanu, Brandon M., Lohbihler, Michelle, Carney, Olivia Sniezek, van Heeringen, Simon, Clijsters, Linda, Sizova, Olga, van Ameijde, Jeroen, Nye, Freya, Habsid, Andrea, Nedyalkova, Lucy, McDonald, Laura, Simpson, Craig, Wybenga-Groot, Leanne, Brown, Kevin R., Nho, Nhi, Suciu, Radu M., Chan, Katherine, Tong, Amy H. Y., Vaz, Frdric M., Evers, Bastiaan, Lesurf, Robert, Papaz, Tanya, Nutter, Lauryl M. J., Protze, Stephanie, Billmann, Maximilian, Costanzo, Michael, Andrews, Brenda J., Myers, Chad L., Mital, Seema, Vernon, Hilary, Brummelkamp, Thijn R., Boone, Charles, Scott, Ian C., Niphakis, Micah J., Strathdee, Douglas, Nijman, Sebastian M. B., Blomen, Vincent A., Moffat, Jason

Issue&Volume: 2025-09-03

Abstract: Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes1. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains1. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro, and its inactivation in cells and mice results in a shift to nCL in serum and tissues. Notably, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth syndrome. This rare genetic disease is characterized by the build-up of MLCL resulting from inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL-remodelling cascade1. We also identified a selective, covalent, small-molecule inhibitor of ABHD18 that rescues TAZ mutant phenotypes in fibroblasts from human patients and in fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.

DOI: 10.1038/s41586-025-09373-5

Source: https://www.nature.com/articles/s41586-025-09373-5