Cell lineage specific mitochondrial resilience during mammalian organogenesis

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 down regulation 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 specific 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. Single-cell RNA-sequencing from whole mice embryos不同器官的线粒体活性存在显著差异，但其产生的具体机制与时间节点尚未明确。本研究证实，涉及核心线粒体基因的细胞谱系特异性表达谱在小鼠发育早期即可出现，其中包括器官形成前就已存在的组织特异性同工型。然而，细胞核的转录特征并非独立于细胞器功能。通过两种不同的线粒体DNA（mtDNA）突变干扰线粒体内蛋白质合成，可诱导产生细胞谱系特异性的代偿反应，其中包含此前未被证实参与细胞器维持的分子通路。我们观察到，已知会加剧外源性线粒体毒素损伤的基因表达出现下调，这表明胚胎发育过程中存在针对线粒体功能障碍的转录适应性调控。这些代偿通路同时具有组织特异性与突变特异性，并受可提升细胞器抗逆能力的特定转录因子（transcription factor）调控。上述通路可能是导致人类线粒体疾病呈现组织特异性特征的关键因素，同时也是器官靶向治疗的潜在靶点。本研究数据集源自完整小鼠胚胎的单细胞RNA测序（single-cell RNA-sequencing）。