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Prenatal Antioxidant Therapy in a Tafazzin Knockout Mouse Model of Barth Syndrome

BACKGROUND: Barth syndrome is a rare X-linked mitochondrial disorder caused by mutations in tafazzin, a transacylase for the final biosynthetic step of cardiolipin. The tafazzin knockout (TAZKO) mouse is a new model of Barth syndrome that exhibits significant lethality in the pre-/perinatal periods, stunted growth, skeletal myopathy, and cardiomyopathy. Excess reactive oxygen species (ROS) may underlie pathogenesis. Prior work from our lab however did not suggest any improvement in the cardiomyopathy of tafazzin-deficient adult mice treated with antioxidants. We hypothesized that prenatal antioxidant therapy may reverse some or many of the multisystem abnormalities.

METHODS: Female TAZ +/- were mated with wildtype male mice to generate TAZKO (TAZ -/y) males. Antioxidant compounds were administered in drinking water: 1) N-acetylcysteine (NAC) – a nonspecific free radical scavenger; and 2) MitoQ – a conjugated molecule that selectively concentrates in mitochondria; 3) Melatonin - an indoleamine with multiple actions including antioxidant properties. We started treatment the first day of mating and continued until weaning. Survival, and functional, ultrastructural, and biochemical assessments were determined.

RESULTS: The expected Mendelian ratio of TAZKO to wildtype males is 50%. In untreated mice, only 11/69 (15.9%) males at weaning were TAZKO (p < 0.0001). Fetal echocardiography at E14.5 showed no differences in cardiac function, or aortic or umbilical blood flows, but mice typically died in the immediate postnatal period. TAZKO mice exhibited stunted growth. Heart histology at E14.5 suggested a thinner compact myocardium with a more porous septum at E14.5, but similar trabeculations in TAZKO and WT embryos. EM micrography of myocardium showed no obvious differences in E14.5 embryos, but abnormal mitochondrial morphology with cytoplasmic lipid droplets were found in TAZKO adult survivors. Only 1 KO male out of 18 (5.6%) survived to weaning with NAC treatment, and so far, no TAZKO pups have been recovered following melatonin treatment. MitoQ-treated TAZKO males trended towards improved survival at weaning (6/19, 31.6%; p=0.12) but remained stunted. MitoQ did not ameliorate the cardiomyopathy in TAZKO mice. Additional detailed histopathology, electron microscopy, and determination of ROS levels are forthcoming.

CONCLUSION: NAC and melatonin do not improve prenatal survival of TAZKO mice, although MitoQ might. MitoQ does not ameliorate the stunted growth or cardiomyopathy in adult TAZKO mice. Experiments are ongoing to determine if ROS are reduced prenatally by these therapies and if the lack of significant benefits are accompanied by persistent subcellular abnormalities

Colin K.L. Phoon1, Paighton C. Miller1, Michael Schlame2, Douglas Strathdee3, Mindong Ren2

  1. Pediatric Cardiology/Pediatrics, New York University Grossman School of Medicine, New York, NY, USA
  2. Anesthesiology/Cell Biology, New York University Grossman School of Medicine, New York, NY, USA
  3. Cancer Research UK Beatson Institute, Glasgow, UK

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