Deficiency in the mouse mitochondrial adenine nucleotide translocator isoform 2 gene is associated with cardiac noncompaction
| Autor: | Jason E. Kokoszka, Alessia Angelin, Grant R. MacGregor, Katrina G. Waymire, Katelyn Sweeney, Adrian Flierl, Douglas C. Wallace |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Organogenesis Mitochondrion Lethal Biochemistry Transgenic Exon Mice Congenital Myocytes Cardiac Developmental Heart Defects biology Adenine nucleotide translocator Gene Expression Regulation Developmental Heart Biological Sciences Null allele Mitochondria Phenotype Embryo Physical Sciences Female Cardiac Heart Defects Congenital Gene isoform Cardiomyopathy Heart Ventricles Biophysics Cre recombinase Mice Transgenic Hypertrabeculation Article 03 medical and health sciences Animals Noncompaction Gene Cell Proliferation Heart Failure Myocytes Integrases Adenine Mammalian Adenine Nucleotide Translocator 2 Biological Transport Cell Biology Embryo Mammalian Molecular biology 030104 developmental biology Mitochondrial permeability transition pore Gene Expression Regulation Genes biology.protein Genes Lethal Mitochondrial Swelling |
| Zdroj: | Biochimica et biophysica acta, vol 1857, iss 8 |
| Popis: | The mouse fetal and adult hearts express two adenine nucleotide translocator (ANT) isoform genes. The predominant isoform is the heart-muscle-brain ANT-isoform gene 1 (Ant1) while the other is the systemic Ant2 gene. Genetic inactivation of the Ant1 gene does not impair fetal development but results in hypertrophic cardiomyopathy in postnatal mice. Using a knockin X-linked Ant2 allele in which exons 3 and 4 are flanked by loxP sites combined in males with a protamine 1 promoter driven Cre recombinase we created females heterozygous for a null Ant2 allele. Crossing the heterozygous females with the Ant2(fl), PrmCre(+) males resulted in male and female ANT2-null embryos. These fetuses proved to be embryonic lethal by day E14.5 in association with cardiac developmental failure, immature cardiomyocytes having swollen mitochondria, cardiomyocyte hyperproliferation, and cardiac failure due to hypertrabeculation/noncompaction. ANTs have two main functions, mitochondrial-cytosol ATP/ADP exchange and modulation of the mitochondrial permeability transition pore (mtPTP). Previous studies imply that ANT2 biases the mtPTP toward closed while ANT1 biases the mtPTP toward open. It has been reported that immature cardiomyocytes have a constitutively opened mtPTP, the closure of which signals the maturation of cardiomyocytes. Therefore, we hypothesize that the developmental toxicity of the Ant2 null mutation may be the result of biasing the cardiomyocyte mtPTP to remain open thus impairing cardiomyocyte maturation and resulting in cardiomyocyte hyperproliferation and failure of trabecular maturation. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. |
| Databáze: | OpenAIRE |
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