A shared pattern of altered gene expression in human embryos affected by mitochondrial diseases.

STUDY QUESTIONDoes mitochondrial deficiency affect human embryonic preimplantation development?SUMMARY ANSWERThe presence of a pathogenic mitochondrial variant triggers changes in the gene expression of preimplantation human embryos, compromising their development, cell differentiation, and survival.WHAT IS KNOWN ALREADYQuantitative and qualitative anomalies of mitochondrial DNA (mtDNA) are reportedly associated with impaired human embryonic development, but the underlying mechanisms remain unexplained.STUDY DESIGN, SIZE, DURATIONTaking advantage of the preimplantation genetic testing for mitochondrial disorders in at-risk couples, we have compared gene expression of 9 human embryos carrying pathogenic variants in either mtDNA genes or nuclear genes encoding mitochondrial protein to 33 age-matched control embryos.PARTICIPANTS/MATERIALS, SETTING, METHODSSingle-embryo transcriptomic analysis was performed on whole human blastocyst embryos donated to research.MAIN RESULTS AND THE ROLE OF CHANCESpecific pathogenic mitochondrial variants downregulate gene expression in preimplantation human embryos [566 genes in oxidative phosphorylation (OXPHOS)-deficient embryos], impacting transcriptional regulators, differentiation factors, and nuclear genes encoding mitochondrial proteins. These changes in gene expression primarily alter OXPHOS and cell survival pathways.LIMITATIONS, REASONS FOR CAUTIONThe number of OXPHOS-deficient embryos available for the study was limited owing to the rarity of this material. However, the molecular signature shared by all these embryos supports the relevance of the findings.WIDER IMPLICATIONS OF THE FINDINGSWhile identification of reliable markers of normal embryonic development is urgently needed in ART, our study prompts us to consider under-expression of the targeted genes reported here, as predictive biomarkers of mitochondrial dysfunction during preimplantation development.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the 'Association Française contre les Myopathies (AFM-Téléthon)' and the 'La Fondation Maladies Rares'. No competing interests to declare.TRIAL REGISTRATION NUMBERN/A.KEYWORDSRNA sequencing, differential gene expression, human embryo development, mitochondrial metabolism, mitochondrial mutation, transcriptome© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.