Journal
SCIENCE ADVANCES
Volume 6, Issue 31, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aba5345
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Funding
- MINECO [SAF2015-65633-R, SAF2016-78114-R, SAF201784494-C2-1-R]
- MINECO-FEDER [SAF2016-79126-R]
- Comunidad de Madrid [IMMUNOTHERCAN-CM B2017/BMD-3733]
- CIBERFES [CB16/10/00282]
- H2020 European Commission (BatCure grant) [666918]
- SOFPI-fellowship from the MINECO
- UK Medical Research Council
- Cancer Research UK (CRUK) [C399/A2291]
- Oxford Biomedical Research Centre
- European Research Council (ERC) [805046-EvoConBiO]
- Pro-CNIC Foundation
- Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency [MDM-20170720]
- ELKARTEK Program [KK-2019/bmG19]
- BBVA Foundation (Ayudas a Equipos de investigacion cientifica Biomedicina 2018)
- [EP/N014529/1]
- EPSRC [EP/N014529/1] Funding Source: UKRI
- MRC [MR/J013617/1] Funding Source: UKRI
- H2020 Societal Challenges Programme [666918] Funding Source: H2020 Societal Challenges Programme
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Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.
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