BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
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BRD4 介导的内质网-线粒体接触位点的表观遗传调控由线粒体复合物 III 控制。
DOI：
10.1101/2024.02.02.578646
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
M
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作者：
Chen,Brandon;Lynn-Nguyen,TheophilusM;Jadhav,Pankaj;Halligan,BenjaminS;Rossiter,NicholasJ;Guerra,RachelM;Koshkin,Sergei;Koo,Imhoi;Morlacchi,Pietro;Hanna,DavidA;Lin,Jason;Banerjee,Ruma;Pagliarini,DavidJ;Patterson,AndrewD;M
细胞器间的通讯对于细胞代谢平衡是至关重要的。内质网和线粒体接触位点（ERMCS）是最丰富的细胞器间相互作用之一。然而，详细了解ERMCS调节机制及其在细胞代谢中的作用受到缺乏允许时间诱导和逆转的工具的限制。通过无偏筛选方法，我们鉴定了fedratinib，一种FDA批准的药物，通过抑制表观遗传修饰剂BRD 4显著增加ERMCS丰度。Fedratinib快速可逆地调节线粒体和ER形态，并改变代谢稳态。此外，ERMCS调节依赖于线粒体电子传递链复合物III功能。fedratinib活性与其他已报道的ERMCS诱导剂的比较揭示了诱导和功能的共同机制，为越来越多的实验观察结果提供了清晰和统一。总之，我们的研究结果揭示了一种新的表观遗传信号通路和一种连接ERMCS和细胞代谢的内源性代谢调节因子。
Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.