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Cell lineage-specific mitochondrial resilience during mammalian organogenesis.

Accepted version
Peer-reviewed

Type

Article

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Authors

Burr, Stephen P 
Klimm, Florian 
Glynos, Angelos 
Prater, Malwina 
Sendon, Pamella 

Abstract

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.

Description

Keywords

OXPHOS, RNA-seq, SCENIC, mitochondria, mt-Ta, mtDNA, organogenesis, single-cell, Animals, Female, Humans, Mice, Pregnancy, Cell Lineage, DNA, Mitochondrial, Mitochondria, Mitochondrial Diseases, Organogenesis, Organ Specificity, Embryonic Development, Embryo, Mammalian

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

Publisher

Elsevier BV
Sponsorship
MRC (MC_UU_00028/7)
Wellcome Trust (212219/Z/18/Z)
MRC (MR/S035699/1)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_UU_00015/4)
MRC (via University College London (UCL)) (MC_PC_21046)
Medical Research Council (MC_UU_00015/7)