Cardiolipin remodeling by TAZ/tafazzin is selectively required for the initiation of mitophagy

Tafazzin (TAZ) is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of TAZ cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. Here we investigated the role of TAZ in regulating mitochondrial function and mitophagy. Using primary mouse embryonic fibroblasts (MEFs) with doxycycline-inducible knockdown of <i>Taz</i>, we showed that TAZ deficiency in MEFs caused defective mitophagosome biogenesis, but not other autophagic processes. Consistent with a key role of mitophagy in mitochondria quality control, TAZ deficiency in MEFs also led to impaired oxidative phosphorylation and severe oxidative stress. Together, these findings provide key insights on mitochondrial dysfunction in Barth syndrome, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for this lethal condition.

TAZ（tafazzin）是一种磷脂转酰酶（phospholipid transacylase），可催化心磷脂（cardiolipin）的重塑过程，而心磷脂是线粒体氧化磷酸化（oxidative phosphorylation）所需的磷脂分子。TAZ基因突变可引发巴德综合征（Barth syndrome），该疾病以线粒体功能障碍与扩张型心肌病（dilated cardiomyopathy）为典型特征，最终导致患者过早死亡。然而，目前学界对巴德综合征中线粒体功能障碍的潜在分子机制仍不甚明晰。本研究探讨了TAZ在调控线粒体功能及线粒体自噬（mitophagy）中的作用。我们使用携带强力霉素诱导型Taz基因敲低体系的原代小鼠胚胎成纤维细胞（primary mouse embryonic fibroblasts, MEFs）开展实验，结果显示，MEFs中TAZ缺失会导致线粒体自噬体（mitophagosome）生成缺陷，但并未影响其他自噬过程。与线粒体自噬作为线粒体质量控制关键环节的研究共识相符，MEFs中TAZ缺失同样会造成氧化磷酸化功能受损以及严重的氧化应激（oxidative stress）。综上，本研究为巴德综合征的线粒体功能障碍机制提供了关键见解，提示通过药理学手段恢复线粒体自噬或可为该致死性疾病提供全新的治疗策略。