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

Author:

Xu XinxiuORCID,Jin Kang,Bais Abha S.,Zhu Wenjuan,Yagi Hisato,Feinstein Timothy N,Nguyen Phong,Criscione Joseph,Liu Xiaoqin,Beutner Gisela,Karunakaran Kalyani B.,Adams Phillip,Kuo Catherine K.,Kostka Dennis,Pryhuber Gloria S.,Shiva Sruti,Ganapathiraju Madhavi K.,Porter George A.,Lin Jiuann-Huey Ivy,Aronow Bruce,Lo Cecilia W.

Abstract

SummaryHypoplastic 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.

Publisher

Cold Spring Harbor Laboratory

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