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 thatcell lineage-specific expression profiles involving essential mitochondrial genes emer ge at an early stage in mouse development,including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were notindependent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNAmutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated inorganellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenousmitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. Thecompensatory pathways were both tissue and mutation specific and under the control of transcription factors which promoteorganelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases andare potential targets for organ-directed treatments.