TFAM knockdown undermines SQSTM1 mRNA stability but retards autophagy flux and inhibits tumor cells proliferation under starvation conditions

Abstract Although starvation stress can alter the homeostasis of mitochondria and promote autophagy, there is still a lack of research focusing on the connection between them. In this study, we found that, accompanied by the upregulation of autophagy flux, the membrane mitochondrial potential (MMP), the content of reactive oxygen species (ROS), the production of ATP, and the copy number of mitochondrial DNA (mt‐DNA) were changed when limiting amino acids supply. We screened and analyzed altered genes related to mitochondrial homeostasis under starvation stress and verified that the expression of mitochondrial transcription factor A (TFAM) was prominently upregulated. Inhibition of TFAM led to the change of mitochondrial function and homeostasis, caused the decrease of SQSTM1 mRNA stability and ATG101 protein level and restricted the autophagy process of cells under amino acid deficient conditions. In addition, the TFAM knockdown and starvation treatment aggravated the DNA damage and reduced proliferation rate of tumor cells. Therefore, our data shows the correlation between mitochondria homeostasis and autophagy, reveals the effect of TFAM on autophagy flux under starvation stress and provides experimental basis for the combined starvation therapy targeting mitochondria to inhibit tumor growth.