Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease with Pulmonary Hypertension and Frailty; 35236094

Lechuga-Vieco, A. ; Latorre-Pellicer, A. (Universidad de Zaragoza) ; Calvo, E. ; Torroja, C. ; Pellico, J. ; Acín-Pérez, R. ; García-Gil, M. L. ; Santos, A. ; Bagwan, N. ; Bonzon-Kulichenko, E. ; Magni, R. ; Benito, M. ; Justo-Méndez, R. ; Simon, A. K. ; Sánchez-Cabo, F. ; Vázquez, J. ; Ruíz-Cabello, J. ; Enríquez, J. A.

Resumen: 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. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Idioma: Inglés

DOI: 10.1161/CIRCULATIONAHA.121.056286

Año: 2022

Publicado en: Circulation 145, 14 (2022), 1084-1101
ISSN: 0009-7322

Factor impacto JCR: 37.8 (2022)

Categ. JCR: PERIPHERAL VASCULAR DISEASE rank: 1 / 68 = 0.015 (2022) - Q1 - T1
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 3 / 143 = 0.021 (2022) - Q1 - T1

Factor impacto CITESCORE: 42.1 - Medicine (Q1)

Factor impacto SCIMAGO: 7.8 - Physiology (medical) (Q1) - Cardiology and Cardiovascular Medicine (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)