LAUSR

Mitochondria dysfunction is the major characteristic of mitophagy, which is essential in mitochondrial quality control. However, excessive mitophagy contributes to cell death in a number of diseases, including ischemic stroke and hepatotoxicity. Insulin‐like growth factor II (IGF‐II) and its receptor (IGF‐IIR) play vital roles in the development of heart failure during hypertension. We found that IGF‐II triggers IGF‐IIR receptor activation, causing mitochondria dysfunction, resulting in mitophagy, and cardiomyocyte cell death. These results indicated that IGF‐IIR activation triggers mitochondria fragmentation, leading to autophagosome formation, and loss of mitochondria content. These results are associated with Parkin‐dependent mitophagy. Additionally, autophagic proteins Atg5, and Atg7 deficiency did not suppress IGF‐IIR‐induced mitophagy. However, Rab9 knockdown reduced mitophagy and maintained mitochondrial function. These constitutive mitophagies through IGF‐IIR activation trigger mitochondria loss and mitochondrial ROS accumulation for cardiomyocyte viability decrease. Together, our results indicate that IGF‐IIR predominantly induces mitophagy through the Rab9‐dependent alternative autophagy.