Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
J Biol Chem. 2012 Jul 20;287(30):25086-97. doi: 10.1074/jbc.M112.340521. Epub 2012 May 14.
Lipidomic regulation of mitochondrial cardiolipin content and molecular species composition is a prominent regulator of bioenergetic efficiency. However, the mechanisms controlling cardiolipin metabolism during health or disease progression have remained elusive. Herein, we demonstrate that cardiac myocyte-specific transgenic expression of cardiolipin synthase results in accelerated cardiolipin lipidomic flux that impacts multiple aspects of mitochondrial bioenergetics and signaling. During the postnatal period, cardiolipin synthase transgene expression results in marked changes in the temporal maturation of cardiolipin molecular species during development. In adult myocardium, cardiolipin synthase transgene expression leads to a marked increase in symmetric tetra-18:2 molecular species without a change in total cardiolipin content. Mechanistic analysis demonstrated that these alterations result from increased cardiolipin remodeling by sequential phospholipase and transacylase/acyltransferase activities in conjunction with a decrease in phosphatidylglycerol content. Moreover, cardiolipin synthase transgene expression results in alterations in signaling metabolites, including a marked increase in the cardioprotective eicosanoid 14,15-epoxyeicosatrienoic acid. Examination of mitochondrial bioenergetic function by high resolution respirometry demonstrated that cardiolipin synthase transgene expression resulted in improved mitochondrial bioenergetic efficiency as evidenced by enhanced electron transport chain coupling using multiple substrates as well as by salutary changes in Complex III and IV activities. Furthermore, transgenic expression of cardiolipin synthase attenuated maladaptive cardiolipin remodeling and bioenergetic inefficiency in myocardium rendered diabetic by streptozotocin treatment. Collectively, these results demonstrate the unanticipated role of cardiolipin synthase in maintaining physiologic membrane structure and function even under metabolic stress, thereby identifying cardiolipin synthase as a novel therapeutic target to attenuate mitochondrial dysfunction in diabetic myocardium.
脂组学调节线粒体心磷脂的含量和分子种类组成是生物能量效率的主要调节因子。然而，在健康或疾病进展过程中控制心磷脂代谢的机制仍然难以捉摸。在此，我们证明了心肌细胞特异性过表达心磷脂合酶会加速心磷脂脂质组学通量，从而影响线粒体生物能量学和信号转导的多个方面。在出生后期间，心磷脂合酶转基因表达导致心磷脂分子种类在发育过程中的时间成熟发生明显变化。在成年心肌中，心磷脂合酶转基因表达导致对称四-18:2 分子种类显著增加，而心磷脂总量不变。机制分析表明，这些变化是由于磷脂酶和转酰基酶/酰基转移酶活性的顺序心磷脂重塑以及磷脂酰甘油含量降低所致。此外，心磷脂合酶转基因表达导致信号代谢物发生改变，包括保护性类二十烷酸 14,15-环氧二十碳三烯酸的显著增加。通过高分辨率呼吸测定法检查线粒体生物能量功能表明，心磷脂合酶转基因表达导致线粒体生物能量效率提高，这表现在使用多种底物增强电子传递链偶联以及复合物 III 和 IV 活性的有益变化。此外，心磷脂合酶的转基因表达减轻了链脲佐菌素处理引起的糖尿病心肌中适应性差的心磷脂重塑和生物能量效率低下。总的来说，这些结果表明心磷脂合酶在维持生理膜结构和功能方面的意外作用，即使在代谢应激下也是如此，从而确定心磷脂合酶作为一种新型治疗靶点，可减轻糖尿病心肌中的线粒体功能障碍。
