The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer.

ABSTRACT: 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/Kras^G12D/+/Trp53R^172H/+ (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.

SUBMITTER: Wang B 

PROVIDER: S-EPMC12589638 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature