Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson’s disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10 , the putative Caenorhabditis elegans ortholog of MBLAC1 , establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10 . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases.

中文翻译：

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神经胶质 swip-10 通过铜离子稳态控制全身线粒体功能、氧化应激和神经元活力


铜 [Cu（I）] 是酶的必需辅助因子，酶支持许多基本细胞功能，包括线粒体呼吸和调节氧化应激。神经元特别依赖于线粒体产生 ATP，许多神经退行性疾病，包括帕金森病，都与线粒体功能减退有关。基因 MBLAC1 编码一种核糖核酸酶，该核糖核酸酶靶向复制依赖性组蛋白的前 mRNA，最近在酵母中发现的可将 Cu（II） 还原为 Cu（I） 的蛋白质，当突变时会破坏 ATP 的产生，提高氧化应激，并严重影响细胞生长。这个过程是否支持高等真核生物的神经元和/或全身生理学尚不清楚。以前，我们确定了 swip-10，即推定的 MBLAC1 的秀丽隐杆线虫直系同源物，确立了神经胶质 swip-10 在限制多巴胺 （DA） 神经元兴奋性和维持 DA 神经元活力中的作用。在这里，我们提供了来自计算建模的证据，表明 SWIP-10 蛋白结构反映了 MBLAC1 的结构，并在预期会破坏组蛋白 RNA 水解的位点定位了功能编码突变的丧失。此外，我们通过遗传学、生化和药理学研究发现，蠕虫中 swip-10 的缺失会对全身 Cu（I） 水平产生负面影响，导致线粒体呼吸和 ATP 产生缺陷、氧化应激增加和神经退化。这些表型可以在 swip-10 突变体中被 Cu（I） 增强分子 elesclomol 和野生型 swip-10 的神经胶质表达抵消。 总之，这些研究揭示了一种神经胶质表达通路，该通路通过调节 Cu（I） 稳态来支持全身线粒体功能和神经元健康，这种机制可能有助于治疗毁灭性神经退行性疾病的治疗策略。