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 downregulation of genes whose expression is known to exacerbate the effects of exogenous mito-chondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic devel-opment. The compensatory pathways were both tissue and mutation specific and under the control of tran-scription 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.

Ämnesord

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

Nyckelord

comprehensive analysis

transcription factors

stress-response

DNA

mutations

rna

biogenesis

disorders

regulator

identity

package

Biochemistry & Molecular Biology

Cell Biology

Publikations- och innehållstyp

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