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Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease

Xu, X and Jin, K and Bais, AS and Zhu, W and Yagi, H and Feinstein, TN and Nguyen, PK and Criscione, JD and Liu, X and Beutner, G and Karunakaran, KB and Rao, KS and He, H and Adams, P and Kuo, CK and Kostka, D and Pryhuber, GS and Shiva, S and Ganapathiraju, MK and Porter, Jr and Lin, J-HI and Aronow, B and Lo, CW (2022) Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease. In: Cell Stem Cell, 29 (5). 840-855.e7.

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Official URL: https://doi.org/10.1016/j.stem.2022.03.003


Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30 mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.

Item Type: Journal Article
Publication: Cell Stem Cell
Publisher: Cell Press
Additional Information: The copyright for this article belongs to the Cell Press.
Keywords: antioxidant; mitochondrial permeability transition pore, cardiac muscle cell; congenital heart malformation; heart failure; human; induced pluripotent stem cell; metabolism; oxidative stress, Antioxidants; Heart Defects, Congenital; Heart Failure; Humans; Induced Pluripotent Stem Cells; Mitochondrial Permeability Transition Pore; Myocytes, Cardiac; Oxidative Stress
Department/Centre: Division of Interdisciplinary Sciences > Supercomputer Education & Research Centre
Date Deposited: 24 Jun 2022 10:22
Last Modified: 24 Jun 2022 10:22
URI: https://eprints.iisc.ac.in/id/eprint/73640

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