@article{Jin2026, 
author = {Xin Jin and Albert M. Li and Man Zhao and Haowen Jiang and Yiren Xiao and Michaela Yip and Stavros Melemenidis and Scott Jackson and Yanan Yang and Cathyrin Simmermaker and Meng-Ning Zhou and Subarna Sinha and Daniel J. Cuthbertson and Erinn B. Rankin and Jiangbin Ye},
title = {Mitochondrial uncoupling inhibits serine catabolism via FTO activation in metastatic breast cancer},
year = {2026},
journal = {Cancer Biology & Medicine},
volume = {23},
number = {9},
pages = {1303-1319},
keywords = {Mitochondria uncoupler, serine catabolism, one-carbon unit metabolism, FTO, m6A, breast cancer, metastasis},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2025.0444},
doi = {10.20892/j.issn.2095-3941.2025.0444},
abstract = {ObjectiveThe mitochondrial serine catabolic pathway (MSCP) supports tumor proliferation and metastasis, yet no therapies target the MSCP. Because cancer cells rely on the MSCP when respiration is suppressed, we hypothesized that reactivating respiration would inhibit the MSCP.MethodsMitochondrial respiration was activated in triple negative breast cancer (TNBC) cells using uncouplers [niclosamide ethanolamine (NEN) and BAM15]. Metabolic activity through the MSCP was assessed using U-13C-serine tracing and expression of key MSCP enzymes (SHMT2, MTHFD2, and MTHFD1L) were evaluated at the mRNA and protein levels. The NAD+:NADH ratio and 2-hydroxyglutarate (2-HG) levels were determined using liquid chromatography-mass spectrometry. The role of m6A RNA demethylase fat mass and obesity-associated protein (FTO) in regulating MSCP enzymes was examined using pharmacologic and genetic approaches. The therapeutic potential of mitochondrial uncoupling was tested in vivo using a lung metastasis model.ResultsActivation of mitochondrial respiration with NEN or BAM15 inhibited MSCP activity, as indicated by reduced labeling of glycine and purines from U-13C-serine. Mitochondrial uncoupling markedly decreased the levels of SHMT2, MTHFD2, and MTHFD1L protein, despite unchanged or elevated mRNA levels. This post-transcriptional suppression was mediated by an increased NAD+:NADH ratio, leading to reduced 2-HG production and subsequent activation of FTO. Inhibition of FTO, either pharmacologically or genetically, restored MSCP enzyme protein levels. Dietary mitochondrial uncoupling significantly suppressed lung metastasis in vivo.ConclusionsThe findings herein demonstrated that mitochondrial uncouplers inhibit MSCP through FTO-dependent m6A demethylation. This work identified mitochondrial uncoupling as a novel and promising therapeutic approach for promoting m6A demethylation and targeting MSCP in metastatic breast cancer.}
}