iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Xu, X.; Jin, K.; Bais, A. S.; Zhu, W.; Yagi, H.; Feinstein, T. N.; Nguyen, P.; Criscione, J.; Liu, X.; Beutner, G.; Karunakaran, K. B.; Adams, P.; Kuo, C. K.; Kostka, D.; Pryhuber, G. S.; Shiva, S.; Ganapathiraju, M.; Porter, G. A.; Lin, J.-H. I.; Aronow, B. J.; Lo, C. W.

doi:10.1101/2021.05.09.443165

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bioRxiv · 10.1101/2021.05.09.443165

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

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Abstract

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

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Xu, X., Jin, K., Bais, A. S., Zhu, W., Yagi, H., Feinstein, T. N., Nguyen, P., Criscione, J., Liu, X., Beutner, G., Karunakaran, K. B., Adams, P., Kuo, C. K., Kostka, D., Pryhuber, G. S., Shiva, S., Ganapathiraju, M., Porter, G. A., Lin, J.-H. I., Aronow, B. J., Lo, C. W.. 2021-05-10. iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome. https://doi.org/10.1101/2021.05.09.443165

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