Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila
Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila
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DOI：
10.1016/j.nbd.2023.106236
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发表时间：
2023-07-28
影响因子：
6.1
通讯作者：
Giorgini，Flaviano
中科院分区：
文献类型：
--
作者：
Campesan，Susanna;del Popolo，Ivana;Giorgini，Flaviano
亨廷顿氏病（HD）是一种致命的神经退行性疾病，治疗选择有限。人类和动物研究表明，代谢和线粒体功能障碍有助于HD发病机制。在这里，我们使用高分辨率呼吸测定法来揭示缺陷的线粒体氧化磷酸化和电子传递能力时，突变亨廷顿蛋白片段是针对神经元或肌肉inDrosophila和发现，增强线粒体功能可以改善这些缺陷。特别是，我们发现，帕金，E3泛素连接酶的线粒体动力学和稳态的关键，共表达产生显着增强线粒体呼吸时，无论是在神经元或肌肉中表达，导致显着的救援HD模型苍蝇的神经变性，生存能力和寿命。将突变HTT靶向肌肉导致更大的线粒体和更高的线粒体质量，而parkin的共表达增加线粒体分裂并降低质量。此外，直接解决HD介导的缺陷，在苍蝇的线粒体电子传递系统，通过重新路由电子绕过线粒体复合物I或复合物III-IV，显着增加线粒体呼吸，并导致在一个惊人的救援所产生的神经元突变亨廷顿蛋白表达的所有表型。这些观察结果表明，绕过受损的线粒体呼吸复合物在HD可能有治疗这种破坏性疾病的治疗潜力。
Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles inDrosophilaand find that enhancing mitochondrial function can ameliorate these defects. In particular, we find that co-expression of parkin, an E3 ubiquitin ligase critical for mitochondrial dynamics and homeostasis, produces significant enhancement of mitochondrial respiration when expressed either in neurons or muscles, resulting in significant rescue of neurodegeneration, viability and longevity in HD model flies. Targeting mutant HTT to muscles results in larger mitochondria and higher mitochondrial mass, while co-expression of parkin increases mitochondrial fission and decreases mass. Furthermore, directly addressing HD-mediated defects in the fly's mitochondrial electron transport system, by rerouting electrons to either bypass mitochondrial complex I or complexes III-IV, significantly increases mitochondrial respiration and results in a striking rescue of all phenotypes arising from neuronal mutant huntingtin expression. These observations suggest that bypassing impaired mitochondrial respiratory complexes in HD may have therapeutic potential for the treatment of this devastating disorder.