Mitochondrial uncoupling inhibits serine catabolism through FTO activation in metastatic breast cancer. (IMAGE)
Caption
Mitochondrial uncoupling inhibits serine catabolism through FTO activation in metastatic breast cancer. Left: The m6A RNA demethylase, FTO, utilizes α-KG as a substrate. Under the Warburg effect, the reduced NAD+:NADH ratio leads to conversion of α-KG to 2-HG. 2-HG, which is structurally similar to α-KG, acts as a competitive inhibitor of FTO. This inhibition results in the accumulation of m6A on target RNAs, including target RNAs encoding the MSCP pathway enzymes, SHMT2, MTHFD2, and MTHFD1L. The resulting upregulation of these enzymes, which are essential for de novo purine biosynthesis, thereby fulfills the metabolic demands of metastatic breast cancer cell proliferation. Right: Mitochondrial uncouplers, a class of compounds that dissipate the proton gradient across the inner mitochondrial membrane, can activate electron transport chain activity and alleviate reductive stress. This activation of the electron transport chain restores the NAD+:NADH ratio, reverses the Warburg effect, and lowers 2-HG levels. Consequently, FTO activity is recovered, leading to decreased m6A methylation on MSCP gene transcripts, reduced expression of the corresponding enzymes, and suppressed metastasis. α-KG, α-ketoglutarate; 2-HG, 2-hydroxyglutarate; m6A, N6-methyladenosine; FTO, fat mass and obesity-associated protein; SHMT2, serine hydroxymethyltransferase 2; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; MTHFD1L, methylenetetrahydrofolate dehydrogenase 1-like.
Credit
Cancer Biology & Medicine
Usage Restrictions
Credit must be given to the creator. Only noncommercial uses of the work are permitted.
License
CC BY-NC