GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs
Author:
Liu Qing1ORCID, Wu Haodi2, Duren Zhana3, Jiang Chao1, Bortle Kevin Van1, Zhao Mingtao4, Guo Hongchao5, Zhu Chenchen1, Luo Qing-Jun6, Zhao Bingqing1, Liu Jun6, Marciano David1, Gruber Joshua1, Lipchik Andrew1, Narasimha Anil1, Watson Nathaniel1, Tsai Ming-Shian1, Furihata Takaaki7, Tian Lei5, Wei Eric1, Li Yingxin2, Steinmetz Lars5, Wong Wing H.5, Kay Mark6, Wu Joseph5ORCID, Snyder Michael8ORCID
Affiliation:
1. Department of Genetics, Stanford University School of Medicine 2. Stanford Cardiovascular Institute, Stanford University School of Medicine 3. Department of Statistics, Stanford University School of Medicine 4. Nationwide Children's Hospital 5. Stanford University 6. Department of Pediatrics, Stanford University School of Medicine 7. Hokkaido University Graduate School of Medicine 8. Stanford University School of Medicine
Abstract
Abstract
Tyrosine kinase inhibitors (TKIs) have been widely used for cancer chemotherapy, but they also cause cardiotoxicities in cancer patients. In this study, we used human stem cells as an in-vitro system to interrogate the mechanisms underlying drug-induced toxicity in differentiated cardiomyocytes, including anticancer tyrosine kinase inhibitor (TKI) drugs, including imatinib, sunitinib, and vandetanib. Sublethal TKI exposure produces multiple effects, including disarranged sarcomere structure, interrupted Ca2+-handling, and impaired mitochondrial function, evident of TKI-induced toxicity in differentiated cardiomyocytes. GATA4-mediated regulatory networks, including key mitochondrial target genes, emerge as significant molecular signatures in integrated analyses of transcriptome and chromatin accessibility dynamics. We find that, on a molecular level, GATA4 acts as a regulatory factor in mitochondrial biogenesis and OXPHOS by directly regulating specific metabolism-related genes, such as PPARGC1A. Functional genomic experiments targeting GATA4 reveals that GATA4 upregulation by CRISPR-activation is able to restore mitochondrial morphology and OXPHOS upon TKI exposure. In addition, we also identified that GATA4 is involved in regulation of mitochondrial biogenesis during early cardiac differentiation; inhibition of GATA4 during differentiation reduces mitochondrial DNA content, ATP production, and OXPHOS in differentiated cardiomyocytes, demonstrating a developmental role of GATA4 in metabolic management during early cardiac differentiation. Altogether, our study identifies a novel link between GATA4 and mitochondria in cardiomyocytes, and identifies GATA4 as a promising therapeutic target for reducing TKI-induced cardiotoxicity for human health.
Publisher
Research Square Platform LLC
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