Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21.
Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21.
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DOI：
10.1016/j.celrep.2018.07.023
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发表时间：
2018-08-07
期刊：
影响因子：
8.8
通讯作者：
Frank S
中科院分区：
文献类型：
--
作者：
Restelli LM;Oettinghaus B;Halliday M;Agca C;Licci M;Sironi L;Savoia C;Hench J;Tolnay M;Neutzner A;Schmidt A;Eckert A;Mallucci G;Scorrano L;Frank S
应激适应对神经元的健康至关重要。虽然线粒体在神经元发育中的基础作用已被证明，但成年神经元如何响应线粒体功能的变化，以及神经元如何感知、信号和响应线粒体及其相互作用的细胞器功能障碍，仍不清楚。在这里，我们证明了神经元特异性的，在体内可诱导的线粒体裂变蛋白Drp1的消融会引起内质网应激，导致整合的应激反应被激活，最终导致细胞因子FGF21的神经元表达。神经源性FGF21的诱导也出现在变态反应和蛋白疾病的小鼠模型中，突显了这种细胞因子作为潜伏性神经退行性疾病早期生物标志物的潜力。综合应激反应(ISR)激活诱导脑内分解代谢细胞因子FGF21在神经变性模型中诱导的FGF21可能是Restelli等人潜在的生物标志物。结果表明，成年小鼠神经元中线粒体裂变蛋白Drp1的缺失激活了多条应激感应通路。这些都集中在整合的应激反应上，导致代谢细胞因子FGF21的神经元特异性表达。FGF21的大脑诱导也发生在机械独立的蛋白质错误折叠相关神经变性的小鼠模型中。
Stress adaptation is essential for neuronal health. While the fundamental role of mitochondria in neuronal development has been demonstrated, it is still not clear how adult neurons respond to alterations in mitochondrial function and how neurons sense, signal, and respond to dysfunction of mitochondria and their interacting organelles. Here, we show that neuron-specific, inducible in vivo ablation of the mitochondrial fission protein Drp1 causes ER stress, resulting in activation of the integrated stress response to culminate in neuronal expression of the cytokine Fgf21. Neuron-derived Fgf21 induction occurs also in murine models of tauopathy and prion disease, highlighting the potential of this cytokine as an early biomarker for latent neurodegenerative conditions. Neuronal Drp1 ablation is sensed by branches of the integrated stress response (ISR) Activation of the ISR induces catabolic cytokine Fgf21 in the brain Brain Fgf21 induced in neurodegeneration models may be a potential biomarker Restelli et al. show that deletion of mitochondrial fission protein Drp1 in adult mouse neurons activates multiple stress-sensing pathways. These converge on the integrated stress response, resulting in neuron-specific expression of metabolic cytokine Fgf21. Cerebral induction of Fgf21 also occurs in mechanistically independent mouse models of protein misfolding-associated neurodegeneration.
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发表时间：
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