Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria

Area of Science:

• Cell Biology
• Molecular Biology
• Cardiovascular Research

Background:

• Mitochondria dysfunction is a hallmark of mitophagy, crucial for cellular quality control.
• Excessive mitophagy contributes to cell death in diseases like ischemic stroke and hepatotoxicity.
• Insulin-like growth factor II (IGF-II) and its receptor (IGF-IIR) are implicated in heart failure during hypertension.

Purpose of the Study:

• To investigate the role of IGF-II/IGF-IIR signaling in cardiomyocyte cell death.
• To elucidate the specific mechanism of mitophagy induced by IGF-IIR activation.

Main Methods:

• Investigated IGF-II-induced mitophagy and cardiomyocyte cell death.
• Analyzed mitochondria fragmentation, autophagosome formation, and mitochondria content loss.
• Examined the involvement of Parkin-dependent mitophagy, Atg5/Atg7 deficiency, and Rab9 knockdown.

Main Results:

• IGF-II triggers IGF-IIR activation, leading to mitochondria dysfunction, mitophagy, and cardiomyocyte death.
• IGF-IIR activation causes mitochondria fragmentation, autophagosome formation, and loss of mitochondria content.
• Mitophagy was Rab9-dependent, as Rab9 knockdown reduced mitophagy and preserved mitochondrial function, while Atg5/Atg7 deficiency did not suppress it.

Conclusions:

• IGF-IIR activation induces cardiomyocyte death predominantly through Rab9-dependent alternative autophagy.
• This pathway involves mitochondria loss and mitochondrial ROS accumulation, decreasing cardiomyocyte viability.
• The findings reveal a novel mechanism linking IGF-IIR signaling to cell death via a specific autophagy pathway.