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TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes.
Nat Commun 2019; 10(1):4671NC

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.

Authors+Show Affiliations

Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Mechanical Engineering, University of Washington, Seattle, WA, 98195, USA. Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Mechanical Engineering, University of Washington, Seattle, WA, 98195, USA. Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA.NIH West Coast Metabolomics Center, University of California Davis, Davis, CA, 95616, USA.Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA. Department of Pathology, University of Washington, Seattle, WA, 98109, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA. Department of Pathology, University of Washington, Seattle, WA, 98109, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.Helsinki University Hospital, 00290, Helsinki, Finland. Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, 00290, Helsinki, Finland.Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, 98109, USA.Covance Genomics Laboratory, Redmond, WA, 98052, USA.Helsinki University Hospital, 00290, Helsinki, Finland. Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, 00290, Helsinki, Finland. Neuroscience Center, University of Helsinki, 00290, Helsinki, Finland.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA. Department of Pathology, University of Washington, Seattle, WA, 98109, USA. Department of Medicine/Cardiology, University of Washington, Seattle, WA, 98109, USA.NIH West Coast Metabolomics Center, University of California Davis, Davis, CA, 95616, USA. Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. Department of Mechanical Engineering, University of Washington, Seattle, WA, 98195, USA. Department of Pathology, University of Washington, Seattle, WA, 98109, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA, 98195, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98109, USA. hannele@u.washington.edu. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. hannele@u.washington.edu. Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA, 98195, USA. hannele@u.washington.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31604922

Citation

Miklas, Jason W., et al. "TFPa/HADHA Is Required for Fatty Acid Beta-oxidation and Cardiolipin Re-modeling in Human Cardiomyocytes." Nature Communications, vol. 10, no. 1, 2019, p. 4671.
Miklas JW, Clark E, Levy S, et al. TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nat Commun. 2019;10(1):4671.
Miklas, J. W., Clark, E., Levy, S., Detraux, D., Leonard, A., Beussman, K., ... Ruohola-Baker, H. (2019). TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nature Communications, 10(1), p. 4671. doi:10.1038/s41467-019-12482-1.
Miklas JW, et al. TFPa/HADHA Is Required for Fatty Acid Beta-oxidation and Cardiolipin Re-modeling in Human Cardiomyocytes. Nat Commun. 2019 Oct 11;10(1):4671. PubMed PMID: 31604922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. AU - Miklas,Jason W, AU - Clark,Elisa, AU - Levy,Shiri, AU - Detraux,Damien, AU - Leonard,Andrea, AU - Beussman,Kevin, AU - Showalter,Megan R, AU - Smith,Alec T, AU - Hofsteen,Peter, AU - Yang,Xiulan, AU - Macadangdang,Jesse, AU - Manninen,Tuula, AU - Raftery,Daniel, AU - Madan,Anup, AU - Suomalainen,Anu, AU - Kim,Deok-Ho, AU - Murry,Charles E, AU - Fiehn,Oliver, AU - Sniadecki,Nathan J, AU - Wang,Yuliang, AU - Ruohola-Baker,Hannele, Y1 - 2019/10/11/ PY - 2018/09/26/received PY - 2019/09/10/accepted PY - 2019/10/13/entrez PY - 2019/10/13/pubmed PY - 2019/10/13/medline SP - 4671 EP - 4671 JF - Nature communications JO - Nat Commun VL - 10 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/31604922/TFPa/HADHA_is_required_for_fatty_acid_beta-oxidation_and_cardiolipin_re-modeling_in_human_cardiomyocytes L2 - http://dx.doi.org/10.1038/s41467-019-12482-1 DB - PRIME DP - Unbound Medicine ER -