2. Academic Validation
  3. PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis

PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis

  • Free Radic Biol Med. 2025 Aug 1:235:95-108. doi: 10.1016/j.freeradbiomed.2025.04.037.
Weibin He 1,  Jieying Wang 2,  Wenlong He 1,  Ling Zeng 1,  Ruowen Zhao 3,  Kailun Qiu 1,  Guang Tong 4,  Zhongchan Sun 5,  Pengcheng He 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University, 510080, Guangzhou, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, 510080, Guangzhou, China.
  • 2 Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University, 510080, Guangzhou, China.
  • 3 School of Medicine, South China University of Technology, 510006, Guangzhou, China.
  • 4 Department of Cardiac Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University, 510080, Guangzhou, China. Electronic address: tongguang@gdph.org.cn.
  • 5 Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University, 510080, Guangzhou, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, 510080, Guangzhou, China. Electronic address: sunzhongchan@gdph.org.cn.
  • 6 Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University, 510080, Guangzhou, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, 510080, Guangzhou, China; Department of Cardiology, Heyuan People's Hospital, 517000, Heyuan, China. Electronic address: gdhpc100@126.com.
PMID: 40280314 DOI: 10.1016/j.freeradbiomed.2025.04.037
Abstract

Doxorubicin (DOX), a potent chemotherapeutic agent, is widely used for treating malignancies but is limited by its cardiotoxic side effects. Mitochondrial dynamics, encompassing fission and fusion processes, play a pivotal role in maintaining cardiomyocyte function under stress, yet their disruption contributes to DOX-induced cardiotoxicity (DIC). While mitochondrial quality control (MQC) mechanisms are implicated in DIC, the specific molecular players remain unclear. Here, we demonstrate that the mitochondrial Phosphatase PGAM5 exacerbates DIC by disturbing mitochondrial dynamics and promoting oxidative stress and Apoptosis. We show that DOX induces PGAM5 cleavage via activation of mitochondrial proteases OMA1 and YME1L1. Overexpression of PGAM5 blocks DOX-induced mitochondrial elongation and instead promotes mitochondrial fragmentation by disrupting the balance between fission and fusion, mediated by inducing DRP1 dephosphorylation at Ser637 and exacerbating MFN2 downregulation. In addition, our findings indicate that PGAM5's Phosphatase activity, rather than its cleavage, mediates the suppression of DOX-induced mitochondrial elongation. However, PGAM5 overexpression fails to enhance mitophagic clearance of dysfunctional mitochondria. Instead, PGAM5 amplifies DOX-induced oxidative stress and cardiomyocyte Apoptosis, without promoting Other regulated cell death (RCD) pathways like Ferroptosis or Pyroptosis. These findings reveal a novel mechanism by which PGAM5 disrupts mitochondrial dynamics and contributes to DIC, highlighting its potential as a therapeutic target for mitigating DOX-induced cardiomyopathy.

Keywords

Apoptosis; Cardiotoxicity; Doxorubicin; Mitochondrial dynamics; PGAM5.

Figures
Products