Mechanism for arrhythmia in mitochondrial tri-functional protein deficient stem cell derived cardiomyocytes Jason W. Miklasa,b and Hannele Ruohola-Bakera,b,c,* aInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA 98109, USA bDepartment of Biochemistry and Bioengineering, University of Washington, Seattle, WA 98195, USA cDepartment of Biochemistry, University of Washington, School of Medicine, Seattle, WA 98195, USA
Mitochondrial trifunctional protein (MTP) deficiency caused by mutation in hydratase subunit A (HADHA) results in impaired long chain fatty acid (FA) oxidation that can result in sudden infant death syndrome (SIDS). To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation by a MicroRNA Maturation Cocktail that upregulates the epigenetic regulator, HOPX. FA challenged HADHA mutant cardiomyocytes undergo sarcomere degradation, mitochondrial swelling and proton gradient loss due to proton leak, resulting in reduced ATP production. Based on SS-31 rescue of proton leak we propose that cardiolipin defects in HADHA cardiomyocytes lead to an observed increase in cytosolic calcium levels and a reduced rate of calcium sequestering. Defective calcium dynamics in HADHA cardiomyocytes resulted in an arrhythmic state, which may lead to SIDS. This study reveals through the first human MTP-deficient cardiac model in vitro how a metabolic defect can lead to cardiac arrhythmias. Keywords: stem cell derived cardiomyocyte, maturation, metabolic disease, mitochondrial trifunctional protein deficiency, cardiolipin, arrhythmia, HOPX, HADHA
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