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Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty

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Ana Victoria Lechuga-Vieco, Ana Latorre-Pellicer, Enrique Calvo, Carlos Torroja, Juan Pellico , Rebeca Acín-Pérez, María Luisa García-Gil, Arnoldo Santos, Navratan Bagwan, Elena Bonzon-Kulichenko, Ricardo Magni, Marina Benito, Raquel Justo-Méndez, Anna Katharina Simon, Fátima Sánchez-Cabo, Jesús Vázquez, Jesús Ruiz-Cabello, José Antonio Enríquez

Original languageEnglish
Pages (from-to)1084-1101
Number of pages18
JournalCirculation
Volume145
Issue number14
Early online date3 Mar 2022
DOIs
Accepted/In press25 Jan 2022
E-pub ahead of print3 Mar 2022
Published5 Apr 2022

Bibliographical note

Funding Information: Dr Lechuga-Vieco was supported by a Predoctoral Fellowship from Ministerio de Ciencia e Innovación (SVP-2013-068089) and by a Postdoctoral Fellowship from the European Molecular Biology Organization (ALTF115-2019). This study was supported by grants to Dr Enríquez from Ministerio de Ciencia e Innovación (grants SAF2015-65633-R and RTI2018-099357-B-I00) and Humand Frontier Science Program (grant RGP0016/2018). Dr Ruíz-Cabello is supported by grants from the Ministerio de Economía, Industria y Competitivida (grant SAF2017-84494-C2-R), Programa Red Guipuzcoana de Ciencia, Tecnología e Información (grant 2018-CIEN-000058-01), and the Gobierno Vasco, Dpto Industria, Innovación, Comercio y Turismo under the ELKARTEK Program (grant KK-2019/bmG19). Dr Ruíz-Cabello received funding from the BBVA Foundation (Ayudas a Equipos de Investigación Científica Biomedicina 2018). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (grant MDM-2017-0720). Dr Santos has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement 796721. Dr Vázquez received funding from Ministerio de Ciencia e Innovación (grants PGC2018-097019-B-I00 and PRB3-IPT17/0019/0003-ISCIII-SGEFI/ERDF, ProteoRed), the Fundació MaratóTV3 (grant 122/C/2015), and “la Caixa” Banking Foundation (project code HR17-00247). The Centro Nacional de Investigaciónes Cardiovasculares is supported by the Instituto de Salud Carlos III, the Ministerio de Ciencia e Innovación, and the Pro Centro Nacional de Investigaciónes Cardiovasculares Foundation and is a Severo Ochoa Center of Excellence. Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved.

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  • CIRCULATIONAHA.121.056286

    CIRCULATIONAHA.121.056286.pdf, 5.22 MB, application/pdf

    Uploaded date:06 Apr 2022

    Version:Final published version

    Licence:CC BY-NC-ND

King's Authors

Abstract

Background:
In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell.

Methods:
We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism.

Results:
We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context.

Conclusions:
Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.

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