Expression data from P28 C10 G58R Dele1 mouse gastrocnemius muscles.

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy. Here, we identified that diverse mitochondrial myopathy models elicit a protective mitochondrial integrated stress response (mt-ISR), mediated by OMA1-DELE1 signaling. The response was similar following disruptions in mtDNA maintenance, from knockout of Tfam, and mitochondrial protein unfolding, from disease-causing mutations in CHCHD10 (G58R and S59L). The preponderance of the response was directed at upregulating pathways for aminoacyl-tRNA biosynthesis, the intermediates for protein synthesis, and was similar in heart and skeletal muscle but more limited in brown adipose challenged with cold stress. Strikingly, models with early DELE1 mt-ISR activation failed to grow and survive to adulthood in the absence of Dele1, accounting for some but not all of OMA1s protection. Notably, the DELE1 mt-ISR did not slow net protein synthesis in stressed striated muscle, but instead prevented loss of translation-associated proteostasis in muscle fibers. Together our findings identify that the DELE1 mt-ISR mediates a stereotyped response to diverse forms of mitochondrial stress and is particularly critical for maintaining growth and survival in early-onset mitochondrial myopathy. This experiment used the Clariom_S_Mouse Microarray from Affymetrix to analyze the effect of Dele1 KO in CHCHD10 G58R mouse model of mitochondrial myopathy/cardiomyopathy. 16 total samples were analyzed (4 biological replicates of each of the 4 different genotypes). Genes with an FDR0.05 and a fold-change 2 were selected.线粒体功能异常可引发包括线粒体肌病在内的多种毁灭性疾病。本研究发现，多种线粒体肌病模型可触发由OMA1-DELE1信号通路介导的保护性线粒体整合应激反应（mitochondrial integrated stress response，mt-ISR）。该反应在线粒体DNA维持功能受损（如Tfam基因敲除）以及线粒体蛋白质解折叠（如CHCHD10基因致病突变G58R和S59L）的模型中均表现一致。该反应主要上调氨酰-tRNA生物合成通路——蛋白质合成的中间产物相关基因，且该现象在心脏与骨骼肌中表现一致，但在受冷应激刺激的棕色脂肪组织中则较为有限。令人意外的是，在缺失Dele1的情况下，早期激活DELE1介导的mt-ISR的模型无法生长并存活至成年，这解释了OMA1所介导的保护作用的一部分，但并非全部。值得注意的是，DELE1介导的mt-ISR并未降低受应激刺激的横纹肌的净蛋白质合成速率，反而阻止了肌纤维中与翻译相关的蛋白质稳态失衡。综上，本研究发现DELE1介导的mt-ISR可介导针对多种线粒体应激的定型化反应，且对早发性线粒体肌病的生长与存活至关重要。本实验采用Affymetrix公司的Clariom_S_Mouse基因芯片，分析Dele1基因敲除在CHCHD10 G58R线粒体肌病/心肌病小鼠模型中的作用。共分析16份样本（4种不同基因型各设置4个生物学重复）。筛选错误发现率（False Discovery Rate，FDR）小于0.05且倍数变化大于等于2的基因。