The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes
The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes
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DOI：
10.1002/emmm.201201739
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发表时间：
2013-02-01
影响因子：
11.1
通讯作者：
Franco, Brunella
中科院分区：
文献类型：
--
作者：
Indrieri, Alessia;Conte, Ivan;Franco, Brunella
线粒体依赖的（内在的）程序性细胞死亡（PCD）是一种重要的同源平衡机制，它选择适合于组织/器官发育的生物能量丰富的细胞。然而，线粒体功能障碍，内在凋亡和发育异常之间的联系尚未得到证实。现在，我们提供的证据表明，非典型的细胞凋亡依赖性细胞凋亡解释的表型小眼线状皮肤病变（MLS），一个X-连锁的发育障碍引起的全细胞色素c型合成酶（HCCS）基因突变。通过利用一个青鳉模型，概括的MLS表型，我们证明，下调hccs，线粒体呼吸链（MRC）的一个重要的球员，通过在大脑和眼睛的非溶酶体依赖的caspase-9激活引起细胞死亡增加。我们还表明，caspase-9的非常规激活发生在线粒体中，由MRC损伤和活性氧（ROS）的过度产生触发。因此，我们建议，HCCS在中枢神经系统（CNS）的发展中起着关键作用，通过调节一种新的非经典启动细胞死亡，并提供了第一个实验证据线粒体功能障碍，内在凋亡和发育障碍之间的机制联系。
Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial-dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holo-cytochrome c-type synthase (HCCS) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders.