A Drosophila model of mitochondrial disease phenotypic heterogeneity
A Drosophila model of mitochondrial disease phenotypic heterogeneity
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线粒体疾病表型异质性的果蝇模型
DOI：
10.1101/2023.12.05.570102
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Granat L
中科院分区：
文献类型：
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作者：
Granat L
影响线粒体功能的基因突变导致原发性线粒体疾病。线粒体疾病是高度异质性的，甚至患有相同线粒体疾病的患者也可以表现出广泛的表型异质性，这是知之甚少的。线粒体呼吸复合物I亚基的突变导致复合物I缺乏，这可能导致严重的神经系统症状和婴儿死亡。然而，一些复杂的I缺乏症患者表现出更温和的症状。在复合物I缺陷中突变的最常见的核基因是高度保守的核心亚基NDUFS 1。为了模拟复合物I缺乏的表型异质性，我们使用了以不同效率靶向果蝇NDUFS 1同源物ND-75的RNAi系。在果蝇神经元中强烈敲除ND-75导致严重的行为表型、寿命缩短、线粒体形态改变、内质网（ER）-线粒体接触减少和未折叠蛋白反应（UPR）激活。相比之下，弱ND-75敲低导致更温和的行为表型和线粒体形态的变化。此外，弱ND-75没有改变ER-线粒体接触或激活UPR。弱和强ND-75敲低导致大脑中重叠但不同的转录反应，弱敲低特异性地影响蛋白体活性和免疫反应基因。代谢也受到弱和强ND-75敲除的不同影响，包括γ-氨基丁酸（GABA）水平，这可能导致ND-75敲除果蝇的神经元功能障碍。几种代谢过程仅受强ND-75敲低的影响，包括戊糖磷酸途径和代谢物2-羟基戊二酸（2-HG），表明2-HG是严重神经线粒体疾病的候选生物标志物。因此，我们的果蝇模型提供了解剖线粒体疾病表型异质性机制的方法。
Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1. To model the phenotypic heterogeneity in complex I deficiency, we used RNAi lines targeting the Drosophila NDUFS1 homolog ND-75 with different efficiencies. Strong knockdown of ND-75 in Drosophila neurons resulted in severe behavioural phenotypes, reduced lifespan, altered mitochondrial morphology, reduced endoplasmic reticulum (ER)-mitochondria contacts and activation of the unfolded protein response (UPR). By contrast, weak ND-75 knockdown caused much milder behavioural phenotypes and changes in mitochondrial morphology. Moreover, weak ND-75 did not alter ER-mitochondria contacts or activate the UPR. Weak and strong ND-75 knockdown resulted in overlapping but distinct transcriptional responses in the brain, with weak knockdown specifically affecting proteosome activity and immune response genes. Metabolism was also differentially affected by weak and strong ND-75 knockdown including gamma-aminobutyric acid (GABA) levels, which may contribute to neuronal dysfunction in ND-75 knockdown flies. Several metabolic processes were only affected by strong ND-75 knockdown including the pentose phosphate pathway and the metabolite 2-hydroxyglutarate (2-HG), suggesting 2-HG as a candidate biomarker of severe neurological mitochondrial disease. Thus, our Drosophila model provides the means to dissect the mechanisms underlying phenotypic heterogeneity in mitochondrial disease.