GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia

• Published in: Free radical biology & medicine Vol. 221; pp. 235 - 244
• Main Authors: Marzook, Hezlin, Gupta, Anamika, Jayakumar, Manju N., Saleh, Mohamed A., Tomar, Dhanendra, Qaisar, Rizwan, Ahmad, Firdos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.08.2024
• Subjects: BNIP3; Cell Hypoxia; Cell Line; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; FOXO3a; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; GSK-3alpha; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitophagy; Mitophagy - genetics; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Parkin; PINK1; Protein Kinases - genetics; Protein Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; PINK1; FOXO3a; Mitophagy; GSK-3alpha; BNIP3; Parkin
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.05.041

Dysregulated autophagy/mitophagy is one of the major causes of cardiac injury in ischemic conditions. Glycogen synthase kinase-3alpha (GSK-3α) has been shown to play a crucial role in the pathophysiology of cardiac diseases. However, the precise role of GSK-3α in cardiac mitophagy remains unknown. Herein, we investigated the role of GSK-3α in cardiac mitophagy by employing AC16 human cardiomyocytes under the condition of acute hypoxia. We observed that the gain-of-GSK-3α function profoundly induced mitophagy in the AC16 cardiomyocytes post-hypoxia. Moreover, GSK-3α overexpression led to increased ROS generation and mitochondrial dysfunction in cardiomyocytes, accompanied by enhanced mitophagy displayed by increased mt-mKeima intensity under hypoxia. Mechanistically, we identified that GSK-3α promotes mitophagy through upregulation of BNIP3, caused by GSK-3α-mediated increase in expression of HIF-1α and FOXO3a in cardiomyocytes post-hypoxia. Moreover, GSK-3α displayed a physical interaction with BNIP3 and, inhibited PINK1 and Parkin recruitment to mitochondria was observed specifically under hypoxia. Taken together, we identified a novel mechanism of mitophagy in human cardiomyocytes. GSK-3α promotes mitochondrial dysfunction and regulates FOXO3a -mediated BNIP3 overexpression in cardiomyocytes to facilitate mitophagy following hypoxia. An interaction between GSK-3α and BNIP3 suggests a role of GSK-3α in BNIP3 recruitment to the mitochondrial membrane where it enhances mitophagy in stressed cardiomyocytes independent of the PINK1/Parkin. [Display omitted] •GSK-3a promotes oxidative stress and mitochondrial dysfunction under hypoxia.•Gain-of-GSK-3α function activates hypoxia-induced mitophagy in cardiomyocytes.•GSK-3α physically interacts with BNIP3 specifically under hypoxia.•GSK-3α inhibits PINK1/Parkin recruitment to mitochondria post-hypoxia.•GSK-3α promotes hypoxia-induces mitophagy through FOXO3a-mediated BNIP3 upregulation.