Expression data from P56 Ckmm-cre Tfam 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 Ckmm-cre Tfam (Tfam mKO) 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.线粒体功能障碍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mtDNA维持障碍（如Tfam敲除）以及线粒体蛋白质错误折叠（如CHCHD10致病性突变G58R与S59L）的情况下均可被诱导。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，在心脏与骨骼肌中表现一致，但在受冷应激挑战的棕色脂肪组织中则较为有限。值得注意的是，在DELE1介导的mt-ISR早期激活的模型中，若缺失Dele1，小鼠无法生长至成年，这部分解释了OMA1的保护作用，但无法涵盖其全部保护效应。尤为关键的是，DELE1介导的mt-ISR并未减缓受应激的横纹肌的净蛋白质合成速率，反而阻止了肌纤维中翻译相关蛋白稳态的丧失。综上，本研究证实DELE1介导的mt-ISR可对多种形式的线粒体应激产生定型化应答，且在早发性线粒体肌病中对维持机体生长与存活至关重要。本实验使用Affymetrix/Applied Biosystems旗下的「Clariom S Assay, mouse」芯片，分析了Dele1敲除对Ckmm-cre Tfam（Tfam条件性敲除，Tfam mKO）线粒体肌病/心肌病小鼠模型的影响。共分析16份样本（4种不同基因型各4次生物学重复）。筛选阈值为错误发现率（false discovery rate, FDR）<0.05且倍数变化（fold-change）>2的基因。