PLK1-mediated PDHA1 phosphorylation drives mitochondrial dysfunction, mitophagy, and cancer progression in Cr(VI)-associated lung cancer

Qiongsi Zhang; Jia Peng; Zhiguo Li; Xiongjian Rao; Derek B Allison; Qi Qiao; Zhuangzhuang Zhang; Yifan Kong; Yanquan Zhang; Ruixin Wang; Jinghui Liu; Xinyi Wang; Chaohao Li; Fengyi Mao; Qing Shao; Tianyan Gao; Xiaoqi Liu

doi:10.1016/j.jbc.2025.110406

PLK1-mediated PDHA1 phosphorylation drives mitochondrial dysfunction, mitophagy, and cancer progression in Cr(VI)-associated lung cancer

J Biol Chem. 2025 Jun 20:110406. doi: 10.1016/j.jbc.2025.110406. Online ahead of print.

Authors

Qiongsi Zhang¹, Jia Peng¹, Zhiguo Li², Xiongjian Rao¹, Derek B Allison³, Qi Qiao⁴, Zhuangzhuang Zhang¹, Yifan Kong¹, Yanquan Zhang¹, Ruixin Wang¹, Jinghui Liu¹, Xinyi Wang¹, Chaohao Li¹, Fengyi Mao¹, Qing Shao⁴, Tianyan Gao⁵, Xiaoqi Liu⁶

Affiliations

¹ Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA.
² Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
³ Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA; Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
⁴ Department of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky 40506, USA.
⁵ Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
⁶ Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA. Electronic address: Xiaoqi.Liu@uky.edu.

PMID: 40544996
DOI: 10.1016/j.jbc.2025.110406

Abstract

Hexavalent chromium (Cr(VI)) is a class I environmental carcinogen that induces lung epithelial cell transformation and promotes lung cancer progression by altering cell cycle regulation and cellular energy metabolism. In this study, we investigated the role of polo-like kinase 1 (PLK1) in Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and found that PLK1 expression was significantly upregulated in these cells, leading to impaired mitochondrial function and enhanced mitophagy, which in turn stimulated cell proliferation both in vitro and in vivo. Mechanistically, we demonstrated that PLK1 directly phosphorylates the pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) at Thr57, leading to its destabilization and disruption of pyruvate dehydrogenase complex (PDHc) integrity. This modification inhibits oxidative phosphorylation (OXPHOS) and induces mitochondrial dysfunction. Furthermore, mitochondrial dysfunction triggers mitophagy and accelerates PDHA1 degradation, establishing a positive feedback loop that amplifies mitochondrial impairment and mitophagy, ultimately promoting cancer cell proliferation. These findings underscore the pivotal role of PLK1 in Cr(VI)-associated cancer progression and offer new insights into potential therapeutic targets to inhibit Cr(VI)-induced tumorigenesis.

Keywords: Hexavalent Chromium (Cr(VI)); Mitochondrial Dysfunction; Mitophagy; Polo-like Kinase 1 (PLK1).