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Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.

Abstract
Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (ΔmtDNA), but there is no direct experimental evidence for this. To determine whether ΔmtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ΔmtDNA (mito-miceΔ). Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%. Our model mouse study clearly showed that a single ΔmtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice.
AuthorsShun Katada, Takayuki Mito, Emi Ogasawara, Jun-Ichi Hayashi, Kazuto Nakada
JournalG3 (Bethesda, Md.) (G3 (Bethesda)) Vol. 3 Issue 9 Pg. 1545-52 (Sep 04 2013) ISSN: 2160-1836 [Electronic] England
PMID23853091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA, Mitochondrial
  • Acyl-CoA Dehydrogenase, Long-Chain
  • Electron Transport Complex IV
Topics
  • Acyl-CoA Dehydrogenase, Long-Chain (deficiency, genetics)
  • Animals
  • Congenital Bone Marrow Failure Syndromes
  • DNA, Mitochondrial (genetics)
  • Disease Models, Animal
  • Electron Transport Complex IV (metabolism)
  • Embryo, Mammalian (metabolism)
  • Kearns-Sayre Syndrome (genetics, pathology)
  • Lipid Metabolism, Inborn Errors (genetics, pathology)
  • Mice
  • Microscopy, Electron
  • Mitochondria (genetics, metabolism)
  • Mitochondrial Diseases (genetics, pathology)
  • Muscular Diseases (genetics, pathology)
  • Phenotype
  • Retina (pathology)
  • Sequence Deletion

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