FOXO3 Activates MFN2 Expression to Maintain the Autophagy Response in Cancer Cells Under Amino Acid Deprivation

The lack of amino acids triggers the autophagic response. Some studies have shown such starvation conditions also induce mitochondrial fusion, revealing a close correlation between the two processes. Although Mitofusin-2 (MFN2) has been demonstrated to play a role in fusion regulation, its role in the autophagic response and the variables that activate MFN2 under stress remain unknown. In this investigation, we screened and confirmed that forkhead box protein O3 (FOXO3) participates in MFN2's expression during short periods of starvation. Luciferase reporter test proved that FOXO3 facilitates MFN2's transcription by binding to its promoter region, and FOXO3 downregulation directly depresses MFN2's expression. Consequently, inhibiting the FOXO3–MFN2 axis results in the loss of mitochondrial fusion, disrupting the normal morphology of mitochondria, impairing the degradation of substrates, and reducing autophagosome accumulation, ultimately leading to the blockage of the autophagy. In conclusion, our work demonstrates that the FOXO3–MFN2 pathway is essential for adaptive changes in mitochondrial morphology and cellular autophagy response under nutritional constraints.