期刊
CIRCULATION
卷 145, 期 14, 页码 1084-1101出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.121.056286
关键词
DNA; mitochondrial; haplotypes; heart diseases; heteroplasmy; hypertension; pulmonary; mice; oxidative phosphorylation
资金
- European Molecular Biology Organization [ALTF115-2019]
- Ministerio de Ciencia e Innovacion [SAF2015-65633-R, RTI2018-099357-B-I00, PGC2018-097019-B-I00, PRB3-IPT17/0019/0003-ISCIII-SGEFI/ERDF, SVP-2013-068089]
- Humand Frontier Science Program [RGP0016/2018]
- Ministerio de Economia, Industria y Competitivida [SAF2017-84494-C2-R]
- Programa Red Guipuzcoana de Ciencia, Tecnologia e Informacion [2018-CIEN-000058-01]
- Gobierno Vasco, Dpto Industria, Innovacion, Comercio y Turismo under the ELKARTEK Program [KK-2019/bmG19]
- BBVA Foundation (Ayudas a Equipos de Investigacion Cientifica Biomedicina 2018)
- Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency [MDM-2017-0720]
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [796721]
- Fundacio MaratoTV3 [122/C/2015]
- la Caixa Banking Foundation [HR17-00247]
- Instituto de Salud Carlos III
- Ministerio de Ciencia e Innovacion
- Pro Centro Nacional de Investigaciones Cardiovasculares Foundation
- Marie Curie Actions (MSCA) [796721] Funding Source: Marie Curie Actions (MSCA)
This study demonstrates that divergent nonpathologic mtDNA heteroplasmy (DNPH) impairs mitochondrial function in critical tissues such as the heart and skeletal muscle, leading to severe pathology in adulthood. It suggests that potential incompatibilities between donor and recipient mtDNA should be considered in medical interventions.
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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