Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency.
Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency.
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DOI：
10.1371/journal.pgen.1010793
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发表时间：
2023-07
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影响因子：
4.5
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中科院分区：
文献类型：
--
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线粒体NADH脱氢酶亚单位的突变会导致线粒体复合体I缺乏症，这是一组严重的神经系统疾病，可能导致婴儿死亡。复杂I缺乏症的发病机制仍然知之甚少，因此目前还没有可用的治疗方法。为了更好地了解潜在的机制，我们利用线粒体复合体I亚单位ND-75(NDUFS1)的敲除来模拟果蝇的复合体I缺乏症。神经元复合体I缺乏会导致运动障碍、癫痫发作和寿命缩短。在细胞水平上，复合体I缺乏不影响ATP水平，但会导致线粒体形态缺陷、内质网-线粒体接触减少和激活内质网未折叠蛋白反应(UPR)。多组分析表明，复合体I缺乏严重扰乱了大脑中的线粒体新陈代谢。我们发现，酵母非质子转运NADH脱氢酶NDI1的表达恢复了线粒体NADH氧化而不是ATP的产生，恢复了复合体I缺乏时大脑中几种关键代谢物的水平。值得注意的是，NDI1的表达还恢复了内质网-线粒体的联系，阻止了UPR的激活，并挽救了由于复合体I缺乏而导致的行为和寿命表型。综上所述，这些数据表明，神经元NADH脱氢酶活性丧失导致的代谢紊乱导致UPR激活，并推动复合体I缺乏的发病机制。线粒体NADH脱氢酶的突变会导致复合体I缺乏症，这是一种线粒体疾病，其特征是严重的神经问题和生命最初几年的死亡。为了了解潜在的机制，我们模拟了果蝇复杂的I缺乏症。神经元中复杂碘缺乏的果蝇在运动、癫痫发作和严重缩短寿命方面存在问题。果蝇神经元中的复合体I缺乏导致线粒体形态改变和线粒体与内质网之间的接触减少，但不影响ATP水平。此外，在复合体I缺乏的神经元中，一种称为未折叠蛋白反应(UPR)的应激信号通路被激活。复杂的碘缺乏也会改变大脑的新陈代谢。值得注意的是，通过表达酵母NDI1酶，恢复了复合体I在神经元中的NADH脱氢酶活性，而不是质子泵能力，恢复了线粒体的形态，阻止了UPR的激活，并挽救了复合体I缺乏的果蝇的行为和寿命表型。我们的数据表明，由于神经元NADH脱氢酶活性丧失导致的代谢紊乱导致了复合体I缺乏症的发病。
Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency. Mutations in the mitochondrial NADH dehydrogenase cause complex I deficiency, a mitochondrial disease characterised by severe neurological problems and death in the first years of life. To understand the underlying mechanisms, we modelled complex I deficiency in the fruit fly Drosophila. Flies with complex I deficiency in neurons have problems with movement, seizures and severely reduced lifespan. Complex I deficiency in Drosophila neurons causes altered mitochondrial morphology and reduced contacts between the mitochondria and endoplasmic reticulum but does not affect ATP levels. Moreover, a stress signalling pathway called the unfolded protein response (UPR) is activated in complex I deficient neurons. Complex I deficiency also alters metabolism in the brain. Remarkably, restoring the NADH dehydrogenase activity but not the proton pumping ability of complex I in neurons, by expressing the yeast NDI1 enzyme, restores mitochondrial morphology, prevents UPR activation and rescues the behavioural and lifespan phenotypes in complex I deficient flies. Our data suggest that metabolic disruption due to loss of neuronal NADH dehydrogenase activity drive pathogenesis in complex I deficiency.
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影响因子：
3.5
作者：
De Vos KJ;Mórotz GM;Stoica R;Tudor EL;Lau KF;Ackerley S;Warley A;Shaw CE;Miller CC
通讯作者：
Miller CC
影响因子：
6.1
作者：
Cherubini, Marta;Lopez-Molina, Laura;Gines, Silvia
通讯作者：
Gines, Silvia
影响因子：
3.3
作者：
Elefant, F;Palter, KB
通讯作者：
Palter, KB
影响因子：
29
作者：
Albrecht, Simone C.;Barata, Ana Gomes;Dick, Tobias P.
通讯作者：
Dick, Tobias P.
影响因子：
4.5
作者：
Duncan OF;Granat L;Ranganathan R;Singh VK;Mazaud D;Fanto M;Chambers D;Ballard CG;Bateman JM
通讯作者：
Bateman JM