TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes

Jason W. Miklas, Elisa Clark, Shiri Levy, Damien Detraux, Andrea Leonard, Kevin Beussman, Megan R. Showalter, Alec T. Smith, Peter Hofsteen, Xiulan Yang, Jesse Macadangdang, Tuula Manninen, Daniel Raftery, Anup Madan, Anu Suomalainen, Deok-Ho Kim, Charles E. Murry, Oliver Fiehn, Nathan J. Sniadecki, Yuliang Wang and Hannele Ruohola-Baker ()
Additional contact information
Jason W. Miklas: University of Washington, School of Medicine
Elisa Clark: University of Washington, School of Medicine
Shiri Levy: University of Washington, School of Medicine
Damien Detraux: University of Washington, School of Medicine
Andrea Leonard: University of Washington, School of Medicine
Kevin Beussman: University of Washington, School of Medicine
Megan R. Showalter: University of California Davis
Alec T. Smith: University of Washington
Peter Hofsteen: University of Washington, School of Medicine
Xiulan Yang: University of Washington, School of Medicine
Jesse Macadangdang: University of Washington, School of Medicine
Tuula Manninen: Helsinki University Hospital
Daniel Raftery: University of Washington
Anup Madan: Covance Genomics Laboratory
Anu Suomalainen: Helsinki University Hospital
Deok-Ho Kim: University of Washington, School of Medicine
Charles E. Murry: University of Washington, School of Medicine
Oliver Fiehn: University of California Davis
Nathan J. Sniadecki: University of Washington, School of Medicine
Yuliang Wang: University of Washington, School of Medicine
Hannele Ruohola-Baker: University of Washington, School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-21

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12482-1

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