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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression
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Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression

机译：溶血脂蛋白酰基转移酶1（ALCAT1）通过调节MFN2表达来控制线粒体DNA保真度和生物发生

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摘要

Oxidative stress causes mitochondrial fragmentation and dysfunction in age-related diseases through unknown mechanisms. Cardiolipin (CL) is a phospholipid required for mitochondrial oxidative phosphorylation. The function of CL is determined by its acyl composition, which is significantly altered by the onset of age-related diseases. Here, we examine a role of acyl-CoA: lysocardiolipin acyltransferase lysocardiolipin acyltransferase 1 (ALCAT1), a lysocardiolipin acyltransferase that catalyzes pathological CL remodeling, in mitochondrial biogenesis. We show that overexpression of ALCAT1 causes mitochondrial fragmentation through oxidative stress and depletion of mitofusin mitofusin 2 (MFN2) expression. Strikingly, ALCAT1 overexpression also leads to mtDNA instability and depletion that are reminiscent of MFN2 deficiency. Accordingly, expression of MFN2 completely rescues mitochondrial fusion defect and respiratory dysfunction. Furthermore, ablation of ALCAT1 prevents mitochondrial fragmentation from oxidative stress by up-regulating MFN2 expression, mtDNA copy number, and mtDNA fidelity. Together, these findings reveal an unexpected role of CL remodeling in mitochondrial biogenesis, linking oxidative stress by ALCAT1 to mitochondrial fusion defect.
机译：氧化应激通过未知机制导致与年龄相关的疾病的线粒体片段化和功能障碍。心磷脂（CL）是线粒体氧化磷酸化所需的磷脂。 CL的功能取决于其酰基组成，而酰基组成会因年龄相关疾病的发作而显着改变。在这里，我们检查了酰基辅酶A的作用：lysocardiolipin酰基转移酶lysocardiolipin酰基转移酶1（ALCAT1），一种能催化病理性CL重塑的线粒体生物发生中的lysocardiolipin酰基转移酶。我们表明，ALCAT1的过表达通过氧化应激和线粒体蛋白的减少而导致线粒体的分裂线粒体2（MFN2）的表达。令人惊讶的是，ALCAT1的过表达还导致mtDNA的不稳定性和消耗，这使人想起了MFN2缺乏症。因此，MFN2的表达完全可以挽救线粒体融合缺陷和呼吸功能障碍。此外，ALCAT1的切除可通过上调MFN2表达，mtDNA拷贝数和mtDNA保真度来防止线粒体片段受到氧化应激的影响。总之，这些发现揭示了CL重塑在线粒体生物发生中的意外作用，将ALCAT1的氧化应激与线粒体融合缺陷相关联。

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    Jia Li; Xiaolei Liu; Huayan Wang; Weiping Zhang; David C. Chan; Yuguang Shi;

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    Shaanxi Center for Stem Cell Engineering and Technology, Northwest A&F University,Yangling, Shaanxi 712100, China,Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033,department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China;

    Shaanxi Center for Stem Cell Engineering and Technology, Northwest A&F University,Yangling, Shaanxi 712100, China;

    Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China;

    Division of Biology, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125;

    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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