Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. The compensatory pathways were both tissue and mutation specific and under the control of transcription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments.

器官之间的线粒体活动明显不同，但尚不清楚这种情况是如何发生的以及何时发生的。在这里，我们显示涉及必需线粒体基因的细胞谱系特异性表达谱出现在小鼠发育的早期阶段，包括器官形成前存在的组织特异性同种型。然而，核转录特征并不独立于细胞器功能。用两种不同的 mtDNA 突变从基因上破坏线粒体内蛋白质合成，诱导细胞谱系特异性代偿反应，包括以前未涉及细胞器维持的分子途径。我们看到基因的下调，其表达已知会加剧外源性线粒体毒素的影响，表明在胚胎发育过程中对线粒体功能障碍的转录适应。补偿途径是组织和突变特异性的，并且在促进细胞器弹性的转录因子的控制下。这些可能有助于表征人类线粒体疾病的组织特异性，并且是器官定向治疗的潜在目标。