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Regulation of mother-to-offspring transmission of mtDNA heteroplasmy

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Title: Regulation of mother-to-offspring transmission of mtDNA heteroplasmy
Authors: Latorre-Pellicer, A
Lechuga-Vieco, AV
Johnston, IG
Hämäläinen, RH
Pellico, J
Justo-Méndez, R
Fernández-Toro, JM
Clavería, C
Guaras, A
Sierra, R
Llop, J
Torres, M
Criado, LM
Suomalainen, A
Jones, NS
Ruíz-Cabello, J
Enríquez, JA
Item Type: Journal Article
Abstract: 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.
Issue Date: 3-Dec-2019
Date of Acceptance: 10-Sep-2019
URI: http://hdl.handle.net/10044/1/74117
DOI: 10.1016/j.cmet.2019.09.007
ISSN: 1550-4131
Publisher: Elsevier BV
Start Page: 1120
End Page: 1130.e5
Journal / Book Title: Cell Metabolism
Volume: 30
Issue: 6
Copyright Statement: Crown Copyright © 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sponsor/Funder: Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: EP/N014529/1
Keywords: embryo
germline selection
heteroplasmy
mitochondria
mitochondrial replacement
mtDNA competition
mtDNA inheritance
Endocrinology & Metabolism
0601 Biochemistry and Cell Biology
1101 Medical Biochemistry and Metabolomics
Publication Status: Published
Open Access location: https://www.sciencedirect.com/science/article/pii/S1550413119305108?via%3Dihub
Online Publication Date: 2019-10-03
Appears in Collections:Mathematics
Applied Mathematics and Mathematical Physics
Faculty of Natural Sciences