Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage
Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage
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DOI：
10.1681/asn.2015060623
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发表时间：
2016-07-01
影响因子：
13.6
通讯作者：
Abe, Takaaki
中科院分区：
文献类型：
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作者：
Suzuki, Takehiro;Yamaguchi, Hiroaki;Abe, Takaaki
线粒体功能障碍导致氧化应激增加和ATP消耗，这与多种肾脏疾病的病因有关，如CKD、AKI和类固醇抵抗性肾病综合征。抗氧化疗法正在研究中，但临床结果尚未确定。最近，我们报道了一种新合成的吲哚衍生物，线粒体酸5 (MA-5)，可以提高线粒体疾病患者的细胞ATP水平和成纤维细胞的存活率。MA-5调节线粒体ATP合成独立于氧化磷酸化和电子传递链。在此，我们进一步研究了MA-5的作用机制。缺血再灌注损伤模型和顺铂肾病模型给予MA-5可改善肾功能。在体外生物能量研究中，MA-5促进ATP的产生，降低线粒体活性氧（ROS）的水平，而不影响线粒体复合物I-IV的活性。进一步的分析显示，MA-5靶向线粒体蛋白mitofilin在内膜的嵴交界处。在Hep3B细胞中，mitofilin的过表达增加了基础ATP水平，而MA-5的处理放大了这一作用。在一种独特的线粒体疾病模型（Mitomice with mitochondria） DNA缺失，模仿典型的人类线粒体疾病表型)中，MA-5改善了减少的心脏和肾脏线粒体呼吸，似乎延长了生存时间，尽管无法进行生存时间的统计分析。这些结果表明，MA-5的功能方式不同于抗氧化治疗，可能成为治疗与线粒体功能障碍相关的心脏和肾脏疾病的新型治疗药物。
Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondria) DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondria respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.