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
N1 - Funding Information:
We thank members of the Ruohola-Baker laboratory for helpful discussions throughout this work. This work is supported by grants from the National Institutes of Health R01GM097372, and R01GM083867 for HRB, 1P01GM081619 for C.M. and H.R.B., R01HL146436 and R01HL135143 for H.R.B. and D.H.K. and the NHLBI Progenitor Cell Biology Consortium (U01HL099997; UO1HL099993) for C.M. and H.R.B. National Science Foundation grants CBET-1509106 and CMMI-1661730 for N.S.J. A.S. was supported by the Academy of Finland and Finnish Foundation for Cardiovascular Research. We would like to thank: Dr. David Marcinek for the SS-31, BGI for their sequencing services, Bruce Conklin (UCSF, Gladstone Institute) for the WTC CRISPRi hiPSCs and pQM plasmid backbone, the Vision Core for their TEM services (P30 EY001730) and Professor Vockley and Dr. El-gharbawy for helpful discussions and advice. Scholarship support from the Wellstone Muscular Dystrophy Cooperative Research Center: U54AR065139 and the NSERC Alexander Graham Bell Graduate Scholarship for J.W.M. A.L. was supported by National Institute of Health grants F32 HL126332. S.L. was supported by the WRF Posdoctoral Fellowship Program and E.C. was supported by an NSF Graduate Research Fellowship.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073181188&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12482-1
DO - 10.1038/s41467-019-12482-1
M3 - Article
C2 - 31604922
AN - SCOPUS:85073181188
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4671
ER -
