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November 22, 2024
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Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease with Pulmonary Hypertension and Frailty

Publicated to:CIRCULATION. 145 (14): 1084-1101 - 2022-04-05 145(14), DOI: 10.1161/CIRCULATIONAHA.121.056286

Authors: Lechuga-Vieco AV; Latorre-Pellicer A; Calvo E; Torroja C; Pellico J; Acín-Pérez R; García-Gil ML; Santos A; Bagwan N; Bonzon-Kulichenko E; Magni R; Benito M; Justo-Méndez R; Simon AK; Sánchez-Cabo F; Vázquez J; Ruíz-Cabello J; Enríquez JA

Affiliations

Centro de Investigación Biomédica en Red de Enfermedades Respiratorias; CIC biomaGUNE; Ikerbasque, Basque Foundation for Science; Universidad Complutense de Madrid - Author
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias; ITC (Ingeniería y Técnicas Clínicas) - Author
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias; King's College London - Author
Centro de Investigación Biomédica en Red Sobre Fragilidad y Envejecimiento Saludable - Author
Centro de Investigación en Red en Enfermedades Cardiovasculares - Author
Centro Nacional de Investigaciones Cardiovasculares Carlos III - Author
Centro Nacional de Investigaciones Cardiovasculares Carlos III; Kennedy Institute of Rheumatology; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias - Author
Facultad de Medicina, Universidad de Zaragoza - Author
Kennedy Institute of Rheumatology - Author
Universidad Complutense de Madrid - Author
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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.

Keywords

Dna, mitochondrialHaplotypesHeart diseasesHeteroplasmyHypertension, pulmonaryMiceOxidative phosphorylation

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 11.61, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-04, the following number of citations:

  • Scopus: 12

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-04:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 49.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 49 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 62.4.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 21 (Altmetric).
  • The number of mentions in news outlets: 7 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.