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 (ANTs) 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 Ant2fl, 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.

MitoBKCa channel is functionally associated with its regulatory β1 subunit in cardiac mitochondria

“…), a regulator of the mPTP (Kokoszka et al . ). Therefore, interactions of mitoBK Ca channels with mitochondrial proteins and complexes may confer novel biophysical properties within the same population of mitochondria.…”

Human adenine nucleotide translocases physically and functionally interact with respirasomes

“…Mutations in ANT2 have also been associated with nonsyndromic intellectual disability (Vandewalle et al , 2013) and cardiac noncompaction (Kokoszka et al , 2016) and its dysregulation associated with a Warburg metabolic phenotype (Maldonado et al , 2016). These diseases have disparate phenotypic manifestations bound by an underlying mitochondrial dysfunction, albeit without a clear molecular explanation.…”

Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD

“…This observation of compensation by ANT4 when Ant1 and Ant2 were deleted from the liver likely explains why Kokoszka and colleagues failed to observe a more severe loss of MPTP activity (16). The Ant2 gene was LoxP-targeted to permit tissue specific deletion because full somatic Ant2 -/mice are embryonic lethal (24).…”