TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes
| Autor: | Shiri Levy, Yuliang Wang, Andrea Leonard, Hannele Ruohola-Baker, Elisa C. Clark, Tuula Manninen, Kevin M. Beussman, Jason W. Miklas, Deok Ho Kim, Oliver Fiehn, Nathan J. Sniadecki, Charles E. Murry, Daniel Raftery, Anup Madan, Xiulan Yang, Jesse Macadangdang, Alec S.T. Smith, Damien Detraux, Anu Suomalainen, Megan R. Showalter, Peter Hofsteen |
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| Přispěvatelé: | STEMM - Stem Cells and Metabolism Research Program, University of Helsinki, Research Programs Unit, HUS Helsinki and Uusimaa Hospital District, University Management, Anu Wartiovaara / Principal Investigator, Neuroscience Center |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Patch-Clamp Techniques Human Embryonic Stem Cells General Physics and Astronomy Mitochondrial trifunctional protein deficiency Mitochondrial trifunctional protein Mitochondrion Cardiovascular Fatty acid beta-oxidation chemistry.chemical_compound 0302 clinical medicine Cardiolipin 2.1 Biological and endogenous factors Myocytes Cardiac RNA-Seq Aetiology lcsh:Science GENE-EXPRESSION Pediatric chemistry.chemical_classification Multidisciplinary biology Mitochondrial Trifunctional Protein Fatty Acids 3. Good health Cell biology Mitochondria Electrophysiology Mechanisms of disease Cardiovascular diseases PLURIPOTENT STEM-CELL lipids (amino acids peptides and proteins) Cardiac Oxidation-Reduction Cardiolipins Science CARDIAC DIFFERENTIATION alpha Subunit General Biochemistry Genetics and Molecular Biology MATURATION Cell Line BARTH-SYNDROME 03 medical and health sciences REVEALS Genetics medicine Humans Author Correction Homeodomain Proteins Myocytes Monolysocardiolipin MICRORNA Tumor Suppressor Proteins Fatty acid General Chemistry MASS-SPECTROMETRY Sudden infant death syndrome medicine.disease HUMAN HEART MicroRNAs 030104 developmental biology chemistry biology.protein lcsh:Q Calcium 3111 Biomedicine Mitochondrial Trifunctional Protein alpha Subunit 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-21 (2019) Nature Communications Nature Communications, vol 10, iss 1 Nature communications, vol 10, iss 1 |
| ISSN: | 2041-1723 |
| Popis: | Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX. Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes. |
| Databáze: | OpenAIRE |
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