Common enzyme takes on a surprising role in preventing cancer

 Researchers at Duke University Medical Center and Wake Forest University School of Medicine have identified ALDH4A1, a mitochondrial proline-metabolizing enzyme, as a third structural component of the mitochondrial pyruvate carrier (MPC) complex. Forming a trimeric assembly with MPC1 and MPC2, ALDH4A1 maintains MPC integrity and facilitates pyruvate import into mitochondria.

Mitochondrial pyruvate import serves as a critical step in cellular energy metabolism, linking cytosolic glycolysis to mitochondrial oxidative phosphorylation. Disruptions in this pathway can promote cancer cell proliferation by increasing cytosolic pyruvate and driving glycolytic metabolism, a phenomenon often associated with the Warburg effect.

Understanding how the MPC complex regulates pyruvate import may reveal metabolic vulnerabilities in cancer.

MPC1 and MPC2, the core subunits of the mitochondrial pyruvate carrier complex, serve as the conduit for pyruvate entry into mitochondria. Identification of additional regulatory components had not been observed until now.

In the study, "ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumor suppression," published in Nature Cell Biology, researchers employed proteoliposome reconstitution, blue-native PAGE, and co-immunoprecipitation assays to investigate whether ALDH4A1 functions as a structural component of the MPC complex.

Mass spectrometry and co-immunoprecipitation assays identified interactions between ALDH4A1 and mitochondrial pyruvate carrier subunits MPC1 and MPC2. Pyruvate uptake was quantified, oxygen consumption revealed mitochondrial coupling efficiency.

Western blotting and immunofluorescence confirmed protein expression and mitochondrial localization. Subcutaneous xenograft models in nude mice evaluated tumor growth under conditions of ALDH4A1 knockdown and overexpression.

Loss of ALDH4A1 promoted in vitro cancer cell phenotypes, including proliferation and migration, and induced soft-agar transformation, indicating anchorage-independent growth.

Xenograft models further demonstrated ALDH4A1's tumor-suppressive function, with ALDH4A1 overexpression restricting tumor volume and knockdown promoting rapid tumor growth.

Treatment with the MPC inhibitor UK5099 disrupted the interaction between ALDH4A1 and the MPC complex while leaving MPC1/2 dimers intact, suggesting potential druggability of the ALDH4A1-MPC interface.

Findings position ALDH4A1 as a structural component of the mitochondrial pyruvate carrier complex, expanding its role beyond proline metabolism to include pyruvate import and TCA cycle entry. By maintaining MPC integrity and pyruvate transport, ALDH4A1 limits cytosolic pyruvate accumulation and mitigates metabolic reprogramming associated with tumorigenesis.

Targeting ALDH4A1's regulatory activity within the MPC complex may hold promise for future metabolic interventions in cancer. Further research is required to explore therapeutic strategies and broader metabolic implications.

More information: Che-Chia Hsu et al, ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression, Nature Cell Biology (2025). DOI: 10.1038/s41556-025-01651-8

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