<p>EZRIN is a key player in assembling and coordinating molecular signaling, acting as a linker between receptors in plasma membrane and the actin cytoskeleton. High EZRIN expression level has been extensively studied and often associated with metastasis and cancer progression. Recent reports independently suggested associations between Ezrin and mitochondrial alterations or apoptotic processes, the mechanism by which Ezrin modulates these events remain largely unclear. Here we report that the lack of EZRIN-mediated EGFR internalization and translocation on mitochondria is critical for mitochondrial metabolism. Ezrin-deficient (Ezrin^−/−) cells exhibit marked impairments in mitochondrial respiratory chain (MRC) activity. These cells also show significantly reduced ATP production and elevated mitochondrial ROS levels, revealing cell metabolism deficit. Furthermore, Ezrin loss induces mitochondrial ROS-mediated apoptosis. In vivo, Medaka fish lacking Ezrin display neuronal cell death associated with inflammation, which appear linked to the compromised mitochondrial metabolism and oxidative stress. Our findings reveal a key mechanism within endo-lysosomal signaling that involves Ezrin and the EGFR/TSC complex. both of which are essential for neuronal homeostasis. In conclusion, our data identify a novel molecular pathway in which the Ezrin/EGFR axis regulates mitochondrial metabolism, thereby supporting cellular energy balance and promoting neuronal cell survival.</p>