Artículo del mes
julio 2022

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

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 Ruíz-Cabello, José Antonio Enríquez
La mezcla de ADN mitocondrial de dos orígenes diferentes puede tener efectos perjudiciales a largo y medio plazo. Esta información es muy valiosa para planear de forma segura los tratamientos de reemplazamiento mitocondrial, destinados a evitar la transmisión de mutaciones patológicas a la descendencia, entre ellos la popularmente conocida como “hijos de tres padres genéticos”. Cualquier estrategia terapéutica que pueda suponer la mezcla de ADN mitocondrial sano de dos individuos debe asegurar la compatibilidad de genomas mitocondriales entre el donante y el receptor.
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.
Keywords: DNA, mitochondrial; haplotypes; heart diseases; heteroplasmy; hypertension, pulmonary; mice; oxidative phosphorylation.
Referencia artículo:
Circulation. 2022 Apr 5;145(14):1084-1101. Epub 2022 Mar 3.
Sobre el grupo investigador
El grupo de investigación GENOXPHOS se centra en el estudio del sistema de fosforilación oxidativa y comprender el papel de las mitocondrias como integradores principales del metabolismo celular. Uno de los principales objetivos del grupo es investigar la contribución de la genética mitocondrial, y su papel en el proceso de envejecimiento saludable.