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

AI Article Synopsis

  • Mitochondrial DNA (mtDNA) is mostly inherited from mothers, and typically there are multiple identical copies in cells; however, some medical techniques can introduce varying mtDNA, creating a state known as divergent nonpathologic mtDNA heteroplasmy (DNPH).
  • Research on DNPH in engineered mice revealed that it disrupts mitochondrial function, causing serious health issues in critical tissues, especially the heart and muscles, which leads to conditions like pulmonary hypertension and heart failure.
  • The severity of these health problems is influenced by the genetic makeup of the nucleus, suggesting that medical practices involving mtDNA should carefully consider donor-recipient compatibility.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969846PMC
http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056286DOI Listing

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