Expression data from adult Dele1 and OMA1 mouse brown adipose tissues (BATs).. Expression data from adult Dele1 and OMA1 mouse brown adipose tissues (BATs).

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 OMA1’s 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/Applied Biosystems to analyze the effect of Dele1 KO and OMA1 KO under cold stress. Overall design: 42 total samples were analyzed (7 biological replicates of each of the 3 different genotypes each in 2 different condition). Genes with an FDR≤0.05 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重症疾病。本研究证实，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）。该反应在两种模型中表现相似：一是由Tfam基因敲除引发的线粒体DNA（mtDNA）维持缺陷，二是由CHCHD10致病突变（G58R与S59L）导致的线粒体蛋白质错误折叠。该反应主要上调氨酰-tRNA生物合成通路——蛋白质合成的关键中间环节——相关基因的表达；该反应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更为有限。值得注意的是，在缺失Dele1的情况下，早期激活DELE1介导的线粒体整合应激反应的模型无法生长并存活至成年，这解释了OMA1所提供保护作用的一部分，但并非全部。尤为关键的是，DELE1介导的线粒体整合应激反应并未减缓受应激刺激的横纹肌的净蛋白质合成速率，反而阻止了肌纤维内与翻译相关的蛋白质稳态失衡。综上，本研究结果表明，DELE1介导的线粒体整合应激反应可对多种形式的线粒体应激产生刻板化应答，且对于早发性线粒体肌病的生长与存活尤为关键。本实验采用Affymetrix/Applied Biosystems旗下的Clariom_S_Mouse基因芯片，分析冷应激条件下Dele1敲除（Dele1 KO）与OMA1敲除（OMA1 KO）对机体的影响。实验整体设计：共分析42份样本，3种不同基因型各设置2种处理条件，每种条件下包含7个生物学重复。最终筛选出错误发现率（False Discovery Rate, FDR）≤0.05且表达倍数变化≥2的差异基因。