GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia.
Free Radic Biol Med
; 221: 235-244, 2024 Aug 20.
Article
en En
| MEDLINE
| ID: mdl-38815772
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
/
Hipoxia de la Célula
/
Proteínas Proto-Oncogénicas
/
Miocitos Cardíacos
/
Glucógeno Sintasa Quinasa 3
/
Ubiquitina-Proteína Ligasas
/
Mitofagia
/
Proteína Forkhead Box O3
/
Proteínas de la Membrana
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article