miR-181a/b downregulation exerts a protective action on mitochondrial disease models
miR-181a/b downregulation exerts a protective action on mitochondrial disease models
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DOI：
10.15252/emmm.201708734
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发表时间：
2019-05-01
影响因子：
11.1
通讯作者：
Franco, Brunella
中科院分区：
文献类型：
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作者：
Indrieri, Alessia;Carrella, Sabrina;Franco, Brunella
线粒体疾病(MD)是一组由氧化磷酸化缺陷引起的破坏性疾病，通常是致命性疾病。尽管线粒体医学最近取得了进展，但对这些疾病仍然没有有效的治疗方法。在这里，我们证明了microRNAs miR-181a和miR-181b(miR-181a/b)调节参与线粒体生物发生和功能的关键基因，并且这些miRNAs的下调通过协调激活线粒体生物发生和有丝分裂来促进视网膜中线粒体的周转。因此，我们在不同的MDS动物模型中测试了miR-181a/b失活的效果，例如伴有线状皮肤病变的小眼球和Leber遗传性视神经病变。我们发现，在所有测试的模型中，miR-181a/b下调强烈保护视网膜神经元免受细胞死亡，并显著改善疾病表型。总之，我们的结果表明miR-181a/b调节线粒体的动态平衡，这些miRNAs可能是治疗以神经元变性为特征的MDS的有效的基因无关的治疗靶点。
Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR-181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber's hereditary optic neuropathy. We found that miR-181a/b downregulation strongly protects retinal neurons from cell death and significantly ameliorates the disease phenotype in all tested models. Altogether, our results demonstrate that miR-181a/b regulate mitochondrial homeostasis and that these miRNAs may be effective gene-independent therapeutic targets for MDs characterized by neuronal degeneration.