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Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy
 
 
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Article

Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation–Contraction Coupling

by
Jarrod Moore
1,
Jourdan Ewoldt
2,
Gabriela Venturini
3,
Alexandre C. Pereira
3,
Kallyandra Padilha
4,
Matthew Lawton
1,
Weiwei Lin
1,
Raghuveera Goel
1,
Ivan Luptak
5,
Valentina Perissi
1,
Christine E. Seidman
3,6,7,
Jonathan Seidman
3,
Michael T. Chin
8,
Christopher Chen
2,9 and
Andrew Emili
1,*,†
1
Center for Network Systems Biology, Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
2
Department of Biomedical Engineering, Boston University, Boston, MA 02218, USA
3
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
4
Laboratory of Genetics and Molecular Cardiology, Clinical Hospital, Faculty of Medicine, University of São Paulo, Sao Paulo 05508-000, Brazil
5
Myocardial Biology Unit, Boston University School of Medicine, Boston, MA 02118, USA
6
Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
7
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
8
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02145, USA
9
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
†
Current address: Knight Cancer Institute, Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR 97239, USA.
Int. J. Mol. Sci. 2023, 24(5), 4724; https://doi.org/10.3390/ijms24054724
Submission received: 21 January 2023 / Revised: 16 February 2023 / Accepted: 20 February 2023 / Published: 1 March 2023
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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Abstract

Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.
Keywords: hypertrophic cardiomyopathy; human induced pluripotent stem-cell-derived cardiomyocytes; myectomy; liquid chromatography–tandem mass spectrometry; phosphoproteomics; metabolomics; network systems biology hypertrophic cardiomyopathy; human induced pluripotent stem-cell-derived cardiomyocytes; myectomy; liquid chromatography–tandem mass spectrometry; phosphoproteomics; metabolomics; network systems biology

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MDPI and ACS Style

Moore, J.; Ewoldt, J.; Venturini, G.; Pereira, A.C.; Padilha, K.; Lawton, M.; Lin, W.; Goel, R.; Luptak, I.; Perissi, V.; et al. Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation–Contraction Coupling. Int. J. Mol. Sci. 2023, 24, 4724. https://doi.org/10.3390/ijms24054724

AMA Style

Moore J, Ewoldt J, Venturini G, Pereira AC, Padilha K, Lawton M, Lin W, Goel R, Luptak I, Perissi V, et al. Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation–Contraction Coupling. International Journal of Molecular Sciences. 2023; 24(5):4724. https://doi.org/10.3390/ijms24054724

Chicago/Turabian Style

Moore, Jarrod, Jourdan Ewoldt, Gabriela Venturini, Alexandre C. Pereira, Kallyandra Padilha, Matthew Lawton, Weiwei Lin, Raghuveera Goel, Ivan Luptak, Valentina Perissi, and et al. 2023. "Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation–Contraction Coupling" International Journal of Molecular Sciences 24, no. 5: 4724. https://doi.org/10.3390/ijms24054724

APA Style

Moore, J., Ewoldt, J., Venturini, G., Pereira, A. C., Padilha, K., Lawton, M., Lin, W., Goel, R., Luptak, I., Perissi, V., Seidman, C. E., Seidman, J., Chin, M. T., Chen, C., & Emili, A. (2023). Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation–Contraction Coupling. International Journal of Molecular Sciences, 24(5), 4724. https://doi.org/10.3390/ijms24054724

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