Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/15225
Title
Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
Author(s)
Lechuga-Vieco, Ana Victoria | Latorre-Pellicer, Ana CNIC | Calvo, Enrique CNIC | Torroja, Carlos CNIC | Pellico, Juan | Acin-Perez, Rebeca CNIC | García-Gil, María Luisa | Santos, Arnoldo CNIC | Bagwan, Navratan CNIC | Bonzon-Kulichenko, Elena CNIC | Magni, Ricardo CNIC | Benito, Marina CNIC | Justo-Méndez, Raquel | Simon, Anna Katharina | Sanchez-Cabo, Fatima CNIC | Vazquez, Jesus CNIC | Ruíz-Cabello, Jesús | Enriquez, Jose Antonio CNIC
Date issued
2022-04-05
Citation
Circulation . 2022 Apr 5;145(14):1084-1101.
Language
Inglés
Document type
journal article
Abstract
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.
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.
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.
Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.
MESH
Frailty | Heart Diseases | Hypertension, Pulmonary | Adult | Animals | DNA, Mitochondrial | Heteroplasmy | Humans | Mice | Mitochondria
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