title: Deficiency in the mouse mitochondrial adenine nucleotide translocator isoform 2 gene is associated with cardiac noncompaction.
abstract: 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.
authors.affiliation: Forensic Biology Section, Alabama Department of Forensic Sciences, Annex C, Mobile, AL 36617, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Kokoszka
authors.affiliation: Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, United States.
authors.forename: Katrina G
authors.initials: KG
authors.lastname: Waymire
authors.affiliation: The Parkinson's Institute, Sunnyvale, CA 94085, United States.
authors.forename: Adrian
authors.initials: A
authors.lastname: Flierl
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Katelyn M
authors.initials: KM
authors.lastname: Sweeney
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Alessia
authors.initials: A
authors.lastname: Angelin
authors.affiliation: Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, United States.
authors.forename: Grant R
authors.initials: GR
authors.lastname: MacGregor
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address: wallaced1@email.chop.edu.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D000225:Adenine / Q000378:metabolism; D033742:Adenine Nucleotide Translocator 2 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*; D019426:Integrases; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D008933:Mitochondrial Swelling / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D038081:Organogenesis; D010641:Phenotype
chemical_list: D033742:Adenine Nucleotide Translocator 2; C045073:Cre recombinase; D019426:Integrases; D000225:Adenine
keywords: Adenine nucleotide translocator 2 (ANT2); Cardiomyopathy; Heart; Hypertrabeculation; Mitochondria; Noncompaction