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GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia.
- Source :
-
Free Radical Biology & Medicine . Aug2024, Vol. 221, p235-244. 10p. - Publication Year :
- 2024
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *HYPOXEMIA
*HEART injuries
*HEART diseases
*PARKIN (Protein)
*GLYCOGEN
Subjects
Details
- Language :
- English
- ISSN :
- 08915849
- Volume :
- 221
- Database :
- Academic Search Index
- Journal :
- Free Radical Biology & Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 177884060
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2024.05.041