FOXO3 Activates MFN2 Expression to Maintain the Autophagy Response in Cancer Cells Under Amino AcidDeprivation.

Abstract

The lack of amino acids triggers the autophagic response. Some studies have shown such starvation conditions also inducemitochondrial fusion, revealing a close correlation between the two processes. Although Mitofusin-2 (MFN2)has been demonstratedto play a role in fusion regulation, its role in the autophagic response and the variables that activateMFN2 under stress remainunknown. In this investigation, we screened and confirmed that forkhead box protein O3 (FOXO3) participatesin MFN2's expression duringshort periods of starvation. Luciferase reporter test proved thatFOXO3 facilitatesMFN2's transcription by binding to its promoter region, and FOXO3 downregulation directly depresses MFN2's expression. Consequently, inhibiting the FOXO3-MFN2 axis resultsin 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.