Higd1a improves respiratory function in the models of mitochondrial disorder
Higd1a improves respiratory function in the models of mitochondrial disorder
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DOI：
10.1096/fj.201800389r
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发表时间：
2020-01-01
期刊：
影响因子：
4.8
通讯作者：
Takashima, Seiji
中科院分区：
文献类型：
--
作者：
Nagao, Takemasa;Shintani, Yasunori;Takashima, Seiji
呼吸链（RC）传输电子以形成线粒体中ATP合成所需的质子动力。RC障碍引起的线粒体疾病几乎没有有效的治疗方法;因此，迫切需要新的治疗策略。我们以前确定Higd 1a作为细胞色素c氧化酶（CcO）在RC的正调节。在这里，我们测试了Higd 1a通过增加线粒体功能障碍模型中的CcO活性而具有有益作用。我们首先通过在斑马鱼缺氧模型中原位测量线粒体ATP浓度（[ATP]（mito））证明了Higd 1a的组织保护作用。心脏特异性Higd 1a过表达减轻了缺氧条件下[ATP]（线粒体）的下降，并保留了斑马鱼的心脏功能。基于体内结果，我们研究了外源性HIGD 1A对线粒体疾病的三种细胞模型的影响;值得注意的是，HIGD 1A改善了呼吸功能，与ATP合成增加相结合，并在所有三种模型中证明了细胞保护作用。最后，酶动力学分析表明，Higd 1a显着增加CcO和细胞色素c之间的反应的最大速度，而不改变它们之间的亲和力，表明Higd 1a是一个积极的调节CcO。这些结果证实了Higd 1a或其模拟物为治疗线粒体疾病提供了治疗选择。
The respiratory chain (RC) transports electrons to form a proton motive force that is required for ATP synthesis in the mitochondria. RC disorders cause mitochondrial diseases that have few effective treatments; therefore, novel therapeutic strategies are critically needed. We previously identified Higd1a as a positive regulator of cytochrome c oxidase (CcO) in the RC. Here, we test that Higd1a has a beneficial effect by increasing CcO activity in the models of mitochondrial dysfunction. We first demonstrated the tissue-protective effects of Higd1a via in situ measurement of mitochondrial ATP concentrations ([ATP](mito)) in a zebrafish hypoxia model. Heart-specific Higd1a overexpression mitigated the decline in [ATP](mito) under hypoxia and preserved cardiac function in zebrafish. Based on the in vivo results, we examined the effects of exogenous HIGD1A on three cellular models of mitochondrial disease; notably, HIGD1A improved respiratory function that was coupled with increased ATP synthesis and demonstrated cellular protection in all three models. Finally, enzyme kinetic analysis revealed that Higd1a significantly increased the maximal velocity of the reaction between CcO and cytochrome c without changing the affinity between them, indicating that Higd1a is a positive modulator of CcO. These results corroborate that Higd1a, or its mimic, provides therapeutic options for the treatment of mitochondrial diseases.