TY - JOUR
T1 - Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development
AU - Lima, Ana
AU - Lubatti, Gabriele
AU - Burgstaller, Jörg
AU - Hu, Di
AU - Green, Alistair P.
AU - Di Gregorio, Aida
AU - Zawadzki, Tamzin
AU - Pernaute, Barbara
AU - Mahammadov, Elmir
AU - Perez-Montero, Salvador
AU - Dore, Marian
AU - Sanchez, Juan Miguel
AU - Bowling, Sarah
AU - Sancho, Margarida
AU - Kolbe, Thomas
AU - Karimi, Mohammad M.
AU - Carling, David
AU - Jones, Nick
AU - Srinivas, Shankar
AU - Scialdone, Antonio
AU - Rodriguez, Tristan A.
N1 - Funding Information:
We thank S. Rothery for guidance and advice with confocal microscopy. The FILM at Imperial College London is supported in part by funding from the Wellcome Trust (grant no. 104931/Z/14/Z) and BBSRC (grant no. BB/L015129/1). We thank J. Elliot and B. Patel from the LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry Facility for support. We are thankful to G. Chennell and A. Sardini for guidance and support with Seahorse experiments. Research in the laboratory of T.A.R. was supported by the MRC project grant (MR/P018467/1) and the BBSRC project grant (BB/S008284/1) and by the British Heart Foundation (BHF) PhD studentships (FS/14/62/31288 and FS/17/64/33476). Work in the laboratory of A.S. is funded by the Helmholtz Association. A.L. was funded by a BHF centre of excellence PhD studentship. S.S. was funded through Wellcome awards 103788/Z/14/Z and 108438/Z/15/Z.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - Cell competition is emerging as a quality-control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated before gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single-cell transcriptional profiling of eliminated mouse epiblast cells, we identify hallmarks of cell competition and mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. Moreover, we show that in the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequences can induce cell competition. Our results suggest that cell competition is a purifying selection that optimizes mitochondrial performance before gastrulation.
AB - Cell competition is emerging as a quality-control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated before gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single-cell transcriptional profiling of eliminated mouse epiblast cells, we identify hallmarks of cell competition and mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. Moreover, we show that in the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequences can induce cell competition. Our results suggest that cell competition is a purifying selection that optimizes mitochondrial performance before gastrulation.
UR - http://www.scopus.com/inward/record.url?scp=85110486433&partnerID=8YFLogxK
U2 - 10.1038/s42255-021-00422-7
DO - 10.1038/s42255-021-00422-7
M3 - Article
AN - SCOPUS:85110486433
SN - 2522-5812
VL - 3
SP - 1091
EP - 1108
JO - Nature Metabolism
JF - Nature Metabolism
IS - 8
ER -