Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy
| Autor: | Rocío Sierra, Iain G. Johnston, Anu Suomalainen, Juan Pellico, Luis M. Criado, Ana Victoria Lechuga-Vieco, Adela Guarás, Ana Latorre-Pellicer, Raquel Justo-Méndez, Jose María Fernández-Toro, Nick S. Jones, Jesús Ruiz-Cabello, José Antonio Enríquez, Miguel Torres, Riikka H. Hämäläinen, Jordi Llop, Cristina Clavería |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Fundación ProCNIC, Centro de Investigación Biomedica en Red - CIBER, Unión Europea. Comisión Europea, Engineering & Physical Science Research Council (EPSRC), Research Programme for Molecular Neurology, University of Helsinki, Research Programs Unit, HUSLAB, Department of Neurosciences, University Management, Anu Wartiovaara / Principal Investigator |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Physiology 0601 Biochemistry and Cell Biology Mice Oogenesis 0302 clinical medicine heteroplasmy Induced pluripotent stem cell Paternal Inheritance Genetics MITOCHONDRIAL-DNA SEGREGATION Phenotype Heteroplasmy Mitochondrial replacement 3. Good health Mitochondria REPLACEMENT mitochondria 1101 Medical Biochemistry and Metabolomics Embryo Female Maternal Inheritance Mitochondrial DNA mtDNA inheritance mtDNA competition Embryonic Development embryo Biology DNA Mitochondrial Cell Line EMBRYOS 03 medical and health sciences Endocrinology & Metabolism Genetic drift germline selection Animals Molecular Biology GENETIC DRIFT Haplotype Cell Biology Fibroblasts Embryo Mammalian Embryonic stem cell Mice Inbred C57BL PATERNAL INHERITANCE 030104 developmental biology Haplotypes Oocytes mitochondrial replacement 1182 Biochemistry cell and molecular biology Germline selection 3111 Biomedicine 030217 neurology & neurosurgery |
| Zdroj: | 1130.e5 Repisalud Instituto de Salud Carlos III (ISCIII) |
| Popis: | mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission. A.V.L.-V. was supported by fellowship SVP-2013-068089 from MCIU. I.G.J. thanks ERC StG EvoConBiO, and a Turing fellowship from the Alan Turing Institute. N.J. thanks EP/N014529/1. SAF2017-84494-C2-R and Programa Red Guipuzcoana de Ciencia, Tecnologıa e Informacion 2018-CIEN-000058-01, and the Basque Government under its ELKARTEK research program (ref: KK-2019/00015) to J.R.-C. The work at CIC biomaGUNE was performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency – Grant No. MDM-2017-0720. This study was supported by grants from the MCNU (SAF2015-65633-R), the EU (UE0/MCA317433), the Biomedical ResearchNetworking Center on Frailty and Healthy Ageing (CIBERFES-ISCiii), and the HFSP agency (RGP0016/2018) to J.A.E. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). AGRADECIENTOS: ProCNIC; Severo Ochoa (SEV-2015-0505) Sí |
| Databáze: | OpenAIRE |
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