Abstract 783: Estrogen Receptor Alpha (ERα) is critical for the maintenance of mitochondrial form and function in the prevention of anthracycline-induced cardiotoxicity

Abstract Cancer remains a leading cause of mortality in the United States, and women’s cancer risk increases after menopause. Anthracyclines (e.g., doxorubicin) are widely used in cancer treatment but their therapeutic value is limited by anthracycline-induced cardiotoxicity (AIC), which can promote irreversible cardiac damage and heart failure. 17-β-estradiol protects against cardiac injury in ovariectomized rodents treated with anthracyclines, thus, we hypothesized that estrogen receptor (ER) α may play a role in safeguarding against AIC. Even without AIC, cardiomyocellular-specific deletion of ERα impairs mitochondrial form and function. This is accompanied by increased fibrosis and reduced cardiac ejection fraction, as determined by echocardiography. Transmission electron microscopy of hearts from ERα knockout mice revealed a marked reduction in mitochondrial cristae density. These cristae are essential structures of the inner mitochondrial membrane, serving as the primary sites for electron transport chain protein localization and oxidative metabolism required for ATP production. Microscopy findings were further supported by RNA sequencing, which indicated differences in the expression of transcripts associated with ATP biosynthesis, oxidative phosphorylation, and mitochondrial respiratory chain complex assembly in the hearts of ERα knockout mice compared to ERα-replete controls. Complementary analysis using Seahorse respirometry on frozen tissue demonstrated a marked reduction in complex I oxygen consumption in ERα knockout mice. With the phenotype observed in heart-specific ERα knockout mice, we hypothesized that doxorubicin-treated HL-1 cardiomyocytes lacking ERα would display increased cell death compared to control cells due to further impairment of mitochondrial function. Indeed, doxorubicin treatment induced a higher rate of cell death in ERα knockout cells vs. control. Key proteins involved in mitochondrial remodeling and mtDNA replication, including Mitofusin 1 (MFN1), Mitofusin 2 (MFN2), Optic Atrophy 1 (OPA1), Dynamin-Related Protein 1 (DRP1), DNA Polymerase Gamma (POLG), Mitochondrial Contact Site and Cristae Organizing System Subunit 25 (MIC25), and Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC1α), were significantly reduced in non-treated ERα knockout HL-1 cells compared to cells with ERα. Combining these findings with the observation that ERα overexpression enhances mitochondrial cristae density, the expression of key mitochondrial-related targets, and mtDNA copy number, our results collectively suggest that ERα is essential for mitochondrial function in the heart and could serve as a therapeutic target to protect against AIC. Citation Format: Thomas K. King, Nicole L. Yang, Arnav Singh, Peter H. Tran, Alice Ma, Emma Yim, Warren C. Tai, Eric H. Yang, Andrea Hevener. Estrogen Receptor Alpha (ERα) is critical for the maintenance of mitochondrial form and function in the prevention of anthracycline-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 783.