Author
Listed:
- Jason W. Miklas
(University of Washington, School of Medicine
University of Washington)
- Elisa Clark
(University of Washington, School of Medicine
University of Washington)
- Shiri Levy
(University of Washington, School of Medicine
University of Washington, School of Medicine)
- Damien Detraux
(University of Washington, School of Medicine
University of Washington, School of Medicine)
- Andrea Leonard
(University of Washington, School of Medicine
University of Washington
University of Washington)
- Kevin Beussman
(University of Washington, School of Medicine
University of Washington
University of Washington)
- Megan R. Showalter
(University of California Davis)
- Alec T. Smith
(University of Washington)
- Peter Hofsteen
(University of Washington, School of Medicine
University of Washington
University of Washington)
- Xiulan Yang
(University of Washington, School of Medicine
University of Washington
University of Washington)
- Jesse Macadangdang
(University of Washington, School of Medicine
University of Washington)
- Tuula Manninen
(Helsinki University Hospital
University of Helsinki)
- Daniel Raftery
(University of Washington)
- Anup Madan
(Covance Genomics Laboratory)
- Anu Suomalainen
(Helsinki University Hospital
University of Helsinki
University of Helsinki)
- Deok-Ho Kim
(University of Washington, School of Medicine
University of Washington)
- Charles E. Murry
(University of Washington, School of Medicine
University of Washington
University of Washington
University of Washington)
- Oliver Fiehn
(University of California Davis
King Abdulaziz University)
- Nathan J. Sniadecki
(University of Washington, School of Medicine
University of Washington
University of Washington
University of Washington)
- Yuliang Wang
(University of Washington, School of Medicine
University of Washington)
- Hannele Ruohola-Baker
(University of Washington, School of Medicine
University of Washington
University of Washington, School of Medicine)
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.
Suggested Citation
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 , 2019.
"TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes,"
Nature Communications, Nature, vol. 10(1), pages 1-21, December.
Handle:
RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12482-1
DOI: 10.1038/s41467-019-12482-1
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