한빛사논문
- 조회442
Gege Yan #,1, Zhenbo Han #,1, Youjeong Kwon #,1, Jordan Jousma 1, Sarath Babu Nukala 1, Benjamin L Prosser 2, Xiaoping Du 1, Sandra Pinho 1, Sang-Bing Ong 3,4,5,6,7, Won Hee Lee 8, Sang-Ging Ong 1,9
1Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago (G.Y., Z.H., Y.K., J.J., S.B.N., X.D., S.P., S.-G.O.).
2Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (B.L.P.).
3Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong (CUHK), China (S.-B.O.).
4Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, CUHK, Hong Kong SAR, China (S.-B.O.).
5Hong Kong Hub of Pediatric Excellence (HK HOPE), Hong Kong Children's Hospital (HKCH), Kowloon Bay, China (S.-B.O.).
6Kunming Institute of Zoology - The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China (S.-B.O.).
7Neural, Vascular, and Metabolic Biology Thematic Research Program, School of Biomedical Sciences, Chinese University of Hong Kong (CUHK), China (S.-B.O.).
8Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix (W.H.L.).
9Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago (S.-G. O.).
#Contributed equally.
Correspondence to: Sang-Ging Ong, PhD, Won Hee Lee, PhD, Sang-Bing Ong, PhD,
Abstract
Background:
Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined.
Methods:
Using human-induced pluripotent stem cells–derived cardiomyocytes (hiPSC-CMs) and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity.
Results:
Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector—ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD+ precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibition, ISRIB, protected human-induced pluripotent stem cell–derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro.
Conclusions:
Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-02-21)
- 국외 연구진
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