Cell lineage-specific mitochondrial resilience during mammalian organogenesis
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2023-03-16
Date Acceptance
2023-01-26
Citation
Cell, 2023, 186 (6), pp.1212-1229.E21
ISSN
0092-8674
Publisher
Elsevier
Start Page
1212
End Page
1229.E21
Journal / Book Title
Cell
Volume
186
Issue
6
Copyright Statement
© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/36827974
PII: S0092-8674(23)00093-4
Subjects
OXPHOS
RNA-seq
SCENIC
mitochondria
mt-Ta
mtDNA
organogenesis
single-cell
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2023-02-23