AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis

Junxiong Zhao; Ting Yang; Jiali Yi; Hongmin Hu; Qi Lai; Liangui Nie; Maojun Liu; Chun Chu; Jun Yang

doi:10.1016/j.isci.2024.109321

AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis

iScience. 2024 Feb 23;27(4):109321. doi: 10.1016/j.isci.2024.109321. eCollection 2024 Apr 19.

Authors

Junxiong Zhao¹, Ting Yang^{2

3}, Jiali Yi⁴, Hongmin Hu¹, Qi Lai^{2

3}, Liangui Nie¹, Maojun Liu¹, Chun Chu³, Jun Yang¹

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
² School of Pharmaceutical Science of University of South China, Hengyang 421000, China.
³ Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
⁴ Department of Cardiology, Hunan University of Medicine General Hospital, Huaihua 418000, China.

Abstract

Doxorubicin induces myocardial injury and fibrosis. Still, no effective interventions are available. AP39 is an H₂S donor that explicitly targets mitochondria. This study investigated whether AP39 could improve doxorubicin-induced myocardial fibrosis. Doxorubicin induced significant myocardial fibrosis while suppressing mitophagy-related proteins and elevating pyroptosis-related proteins. Conversely, AP39 reverses these effects, enhancing mitophagy and inhibiting pyroptosis. In vitro experiments revealed that AP39 inhibited H9c2 cardiomyocyte pyroptosis, improved doxorubicin-induced impairment of mitophagy, reduced ROS levels, ameliorated the mitochondrial membrane potential, and upregulated AMPK-ULK1-FUNDC1 expression. In contrast, AMPK inhibitor (dorsomorphin) and ULK1 inhibitor (SBI-0206965) reversed AP39 antagonism of doxorubicin-induced FUNDC1-mediated impairment of mitophagy and secondary cardiomyocyte pyroptosis. These results suggest that mitochondria-targeted H₂S can antagonize doxorubicin-induced pyroptosis and impaired mitophagy in cardiomyocytes via AMPK-ULK1-FUNDC1 and ameliorated myocardial fibrosis and remodeling.

Keywords: Health sciences; Toxic substance; Toxicology.