Bo Wang, Xinyu Han, Xianlong Lin, Jinjing Wang, Chang You, Keke Chen, Yu Chen, Fan‐hao Meng, Huihui Jiang, Fulong Zheng, Yiqing Zhang, Jinya Lyu, Jinya Lyu, Yuxiao Bai, Xiaoning Qu, Danyi Zhou, Minghua Jiang, Wei Cui, Jianxin Lyu, Jianxin Lyu, Hezhi Fang
Reshaping metabolic compartmentalization is frequently observed in cancer cells, however, the underlying mechanisms and physiological implications are less known. Here, we show that pancreatic ductal adenocarcinoma (PDAC) patients with low integral membrane protein SMIM4 expression exhibits a poor prognosis and reduces oxidative stress in tumors, which can be confirmed in cultured human PDAC cells and mice Pdx1-Cre/KrasG12D/+/Trp53R172H/+ (KPC) cells. Mechanistically, SMIM4 interacts with and facilitates the assembly of SLC25A1-containing complexes, enabling SLC25A1-mediated malate/citrate exchange. Depleting SMIM4 has little effect on mitochondrial respiration but impairs the assembly of SLC25A1-containing complexes, thereby reshaping of malate compartmentalization. This shift promotes NADPH generation through increased cytosolic conversion of malate to pyruvate, protecting cells from glucose deprivation-induced apoptosis. Moreover, PDAC cells with low level of SMIM4 are resistant to RSL3-induced toxicity, indicating that PDAC tumors with high SMIM4 expression are promising candidates for treatment with oxidative stress inducers. Metabolic compartmentalization changes are common in cancer, but their mechanisms remain unclear. Here, the authors show that low expression of the integral membrane protein SMIM4 in pancreatic cancer reshapes malate metabolism and promotes survival under glucose deprivation and RSL3-induced toxicity.