Summary of study ST001246

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, where it has been assigned Project ID PR000833. The data can be accessed directly via it's Project DOI: 10.21228/M8110J This work is supported by NIH grant, U2C- DK119886.


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Study IDST001246
Study TitleTFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes (part-I)
Study SummaryMitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome (SIDS) with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via a novel, engineered MicroRNA Maturation Cocktail (MiMaC) that upregulated the epigenetic regulator, HOPX. Fatty acid challenged MiMaC treated HADHA mutant cardiomyocytes manifested the disease phenotype: defective calcium dynamics and repolarization kinetics which resulted in a pro-arrhythmic state. Single cell RNA-seq revealed a novel cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gave rise to mature-like cardiomyocytes in control cells but, mutant cells transitioned to a pathological state with reduced fatty acid beta-oxidation (FAO), reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that TFPa/HADHA, a MLCL-AT-like enzyme, is required for FAO and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.
University of California, Davis
Last NameShowalter
First NameMegan
AddressUC Davis Genome Center, room 1313, 451 Health Sci Drive
Submit Date2019-08-26
Raw Data AvailableYes
Raw Data File Type(s).raw
Analysis Type DetailLC-MS
Release Date2019-09-06
Release Version1
Megan Showalter Megan Showalter application/zip

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Collection ID:CO001308
Collection Summary:hESC and hiPSC and cardiac differentiation: The hESC line RUES2 (NIHhESC-09-0013) and hiPSC line WTC #11, previously derived in the Conklin laboratory 83, were cultured on Matrigel growth factor-reduced basement membrane matrix (Corning) in mTeSR media (StemCell Technologies). A monolayer-based directed differentiation protocol was followed to generate hESC-CMs and hiPSC-CMs, as done previously 25. hiPSC-CM cardiolipin assay was done with a small molecule monolayer-based directed differentiation protocol, as done previously 84. 15 days after differentiation hPSC-CMs were enriched for the cardiomyocyte population using a lactate selection process 85. We generated cardiomyocyte populations ranging from 40-60% that were then enriched to 75-80% cardiomyocytes after 4 days of lactate enrichment. METABOLITE EXTRACTION: 1 million cells were extracted with 225 ┬Ál of methanol, after enzymatic lifting from cell culture plates.
Sample Type:Cultured cells