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DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
The EMBO Journal ( IF 9.4 ) Pub Date : 2024-10-08 , DOI: 10.1038/s44318-024-00242-x
Hsin-Pin Lin,Jennifer D Petersen,Alexandra J Gilsrud,Angelo Madruga,Theresa M D'Silva,Xiaoping Huang,Mario K Shammas,Nicholas P Randolph,Kory R Johnson,Yan Li,Drew R Jones,Michael E Pacold,Derek P Narendra

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

中文翻译:


DELE1 维持肌肉蛋白质稳态,以促进线粒体肌病的生长和存活。



线粒体功能障碍会导致毁灭性的疾病,包括线粒体肌病,但肌肉如何感知和适应线粒体功能障碍尚不清楚。在这里,我们使用了线粒体肌病的不同小鼠模型来表明线粒体功能障碍的信号起源于线粒体内部。线粒体蛋白 OMA1 和 DELE1 感应线粒体内膜的破坏,并作为响应激活线粒体综合应激反应 (mt-ISR) 以增加蛋白质合成的构建块。在没有 mt-ISR 的情况下,肌肉中的蛋白质合成失调,导致蛋白质错误折叠,患有早发性线粒体肌病的小鼠无法生长和存活。mt-ISR 在 mtDNA 维持 (Tfam 敲除) 和线粒体蛋白错误折叠 (CHCHD10 G58R 和 S59L 敲入) 中断后相似,但在富含线粒体的组织之间存在异质性,在心脏和骨骼肌中观察到广泛的基因表达变化,在肝脏和棕色脂肪组织中观察到有限的变化。综上所述,我们的研究结果确定 DELE1 mt-ISR 介导对不同形式的线粒体应激的类似反应,对于维持早发性线粒体肌病的生长和存活至关重要。
更新日期:2024-10-08
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