PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death

Byeong Geun Seok; Eunhee Park; Young-Jun Park; Hyuk Nam Kwon; Su Wol Chung

doi:10.5483/BMBRep.2024-0139

BMB Reports

PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death

Byeong Geun Seok¹, Eunhee Park¹, Young-Jun Park^2,3, Hyuk Nam Kwon¹, Su Wol Chung ^1,4,*

¹Department of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 44610, ²Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, ³Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34113, ⁴ Brain Korea 21 Project, University of Ulsan College of Medicine, University of Ulsan, Seoul 05505, Korea

Correspondence to: *Tel: +82-52-259-1641; Fax: +82-52-259-1694; E-mail: swchung@ulsan.ac.kr

Received: August 29, 2024; Revised: September 9, 2024; Accepted: December 12, 2024; Published online: January 22, 2025.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT: A type of programmed cell death called ferroptosis is defined by increased iron-dependent lipid peroxidation. Mitochondria play a central role in iron metabolism. Mitochondrial defects include decreased cristae density, membrane rupture, and decreased mitochondrial membrane density, which occur as a result of ferroptosis. One of the important regulator of mitochondrial biogenesis is PGC1α. While recent studies have begun to explore the association between PGC1α and ferroptosis, the specific role of PGC1α in erastin-induced mitochondrial dysfunction during ferroptotic cell death has not been fully elucidated. In this study, we demonstrate for the first time that PGC1α is a key regulator of erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis in HT1080 fibrosarcoma cells. In this study, we examined PGC1α function in ferroptosis. Erastin, an inducer of ferroptosis, boosted the expression of PGC1α. Moreover, PGC1α down-regulation reduced erastin-induced ferroptosis. The most important biochemical feature of ferroptosis is the increase in iron ion (Fe²⁺)-dependent lipid peroxide (LOOH) concentration. Mitochondrial-dependent lipid peroxidation was abolished by PGC1α downregulation. In addition, PGC1α was induced during mitochondrial dysfunction in erastin-induced ferroptosis. Mitochondrial membrane potential loss and mitochondrial ROS production associated with erastin-induced mitochondrial dysfunction were blocked by PGC1α inhibition. In addition, erastin-induced lipid peroxidation in HT1080 fibrosarcoma cells was regulated by PGC1α inhibitor. This phenomenon was also consistent in HT1080 cells transfected with PGC1α shRNA transfected cells. Taken together, these results suggest that PGC1α is a key factor in erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis cell death.; Keywords: Erastin, Ferroptotic cell death, PGC1α, ROS, Mitochondrial dysfunction