Ras-ERK-ETS inhibition alleviates neuronal mitochondrial dysfunction by reprogramming mitochondrial retrograde signaling.
Ras-ERK-ETS inhibition alleviates neuronal mitochondrial dysfunction by reprogramming mitochondrial retrograde signaling.
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DOI：
10.1371/journal.pgen.1007567
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发表时间：
2018-07
期刊：
影响因子：
4.5
通讯作者：
Bateman JM
中科院分区：
文献类型：
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作者：
Duncan OF;Granat L;Ranganathan R;Singh VK;Mazaud D;Fanto M;Chambers D;Ballard CG;Bateman JM
线粒体功能障碍激活线粒体逆行信号通路，导致基因表达发生大规模变化。神经元中的线粒体逆行信号传导尚不清楚，逆行信号传导是否会导致细胞功能障碍或具有保护作用尚不清楚。我们发现，抑制 Ras-ERK-ETS 信号传导可部分逆转逆行转录反应，从而减轻神经元线粒体功能障碍。我们开发了一种新型遗传筛选来识别改变果蝇线粒体功能障碍的基因。敲除本次筛选中确定的基因之一 Ras-ERK-ETS 通路转录因子 Aop，可以减轻神经系统中线粒体功能障碍的破坏性影响。 Ras-ERK-ETS 信号传导的抑制还可恢复与线粒体功能障碍相关的人类疾病的果蝇模型的功能。重要的是，Ras-ERK-ETS 通路抑制部分逆转了线粒体逆行转录反应。因此，线粒体逆行信号传导可能通过基因表达的错误调节导致神经元功能障碍。线粒体功能丧失会激活线粒体逆行信号通路，导致核基因转录发生大规模变化。人们对神经系统中的逆行信号传导以及转录变化如何影响神经元功能知之甚少。在这里，我们将 Ras-ERK-ETS 信号确定为果蝇神经系统中一种新型线粒体逆行信号通路。 Ras-ERK-ETS 信号传导的抑制可改善线粒体疾病果蝇模型中的神经元功能。因此，靶向 Ras-ERK-ETS 信号传导可能对线粒体疾病患者具有治疗潜力。使用转录组学方法，我们发现 Ras-ERK-ETS 信号传导的抑制部分逆转了线粒体逆行转录反应。因此，令人惊讶的是，线粒体逆行转录反应导致神经元功能障碍。
Mitochondrial dysfunction activates the mitochondrial retrograde signaling pathway, resulting in large scale changes in gene expression. Mitochondrial retrograde signaling in neurons is poorly understood and whether retrograde signaling contributes to cellular dysfunction or is protective is unknown. We show that inhibition of Ras-ERK-ETS signaling partially reverses the retrograde transcriptional response to alleviate neuronal mitochondrial dysfunction. We have developed a novel genetic screen to identify genes that modify mitochondrial dysfunction in Drosophila. Knock-down of one of the genes identified in this screen, the Ras-ERK-ETS pathway transcription factor Aop, alleviates the damaging effects of mitochondrial dysfunction in the nervous system. Inhibition of Ras-ERK-ETS signaling also restores function in Drosophila models of human diseases associated with mitochondrial dysfunction. Importantly, Ras-ERK-ETS pathway inhibition partially reverses the mitochondrial retrograde transcriptional response. Therefore, mitochondrial retrograde signaling likely contributes to neuronal dysfunction through mis-regulation of gene expression. Loss of mitochondrial function activates the mitochondrial retrograde signaling pathway resulting in large scale changes in nuclear gene transcription. Very little is known about retrograde signaling in the nervous system and how the transcriptional changes affect neuronal function. Here we identify Ras-ERK-ETS signaling as a novel mitochondrial retrograde signaling pathway in the Drosophila nervous system. Inhibition of Ras-ERK-ETS signaling improves neuronal function in Drosophila models of mitochondrial disease. Targeting Ras-ERK-ETS signaling may therefore have therapeutic potential in mitochondrial disease patients. Using a transcriptomic approach, we find that inhibition of Ras-ERK-ETS signaling partially reverses the mitochondrial retrograde transcriptional response. Surprisingly therefore, the mitochondrial retrograde transcriptional response contributes to neuronal dysfunction.
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影响因子：
64.5
作者：
Homem, Catarina C. F.;Steinmann, Victoria;Knoblich, Juergen A.
通讯作者：
Knoblich, Juergen A.
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：
9.2
作者：
Chen, FL;Rebay, I
通讯作者：
Rebay, I
影响因子：
14.9
作者：
Attrill H;Falls K;Goodman JL;Millburn GH;Antonazzo G;Rey AJ;Marygold SJ;FlyBase Consortium
通讯作者：
FlyBase Consortium
影响因子：
21.3
作者：
通讯作者：
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