Expression data from P28 C10 G58R Dele1 mouse hearts

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 Assay, mouse" from Affymetrix/Applied Biosystems 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致死性疾病。本研究证实，多种线粒体肌病模型可激活由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）。该应激反应在两类线粒体功能紊乱模型中表现一致：一类为Tfam敲除导致的线粒体DNA（mitochondrial DNA, mtDNA）维持功能障碍，另一类为CHCHD10致病突变（G58R与S59L）引发的线粒体蛋白质错误折叠。该应激反应的核心效应为上调氨酰-tRNA生物合成通路——这是蛋白质合成的关键上游通路——其在心脏与骨骼肌中表达模式一致，但在受冷应激刺激的棕色脂肪组织中则较为局限。值得注意的是，在Dele1敲除的条件下，早期激活DELE1介导的mt-ISR的模型无法正常生长并存活至成年，这仅能部分解释OMA1所介导的保护效应，而非全部。尤为关键的是，DELE1介导的mt-ISR并未减缓受应激横纹肌的整体蛋白质合成速率，反而阻止了肌纤维中与翻译过程相关的蛋白质稳态失衡。综上，本研究结果表明，DELE1介导的mt-ISR可介导机体对多种类型线粒体应激的模式化应答，且对于维持早发性线粒体肌病的生长与存活至关重要。本实验采用Affymetrix/Applied Biosystems公司的小鼠Clariom S检测试剂盒（Clariom S Assay, mouse），分析Dele1敲除对线粒体肌病/心肌病CHCHD10 G58R小鼠模型的影响。本研究共纳入16份样本进行分析（4种不同基因型各设置4个生物学重复），最终筛选出错误发现率（False Discovery Rate, FDR）≤0.05且倍数变化≥2的差异基因。