Revelations About an Enzyme's Unexpected Role in Cancer Prevention

Recent research from Duke University Medical Center and Wake Forest University School of Medicine has uncovered a novel function of the mitochondrial enzyme ALDH4A1, traditionally known for its role in proline metabolism. This enzyme has been identified as a critical structural component of the mitochondrial pyruvate carrier (MPC) complex, which includes the core subunits MPC1 and MPC2. By forming a trimeric assembly with these subunits, ALDH4A1 helps preserve the integrity of the MPC complex, facilitating the import of pyruvate into mitochondria.

Pyruvate import is a pivotal step in cellular energy metabolism, linking glycolysis to mitochondrial oxidative phosphorylation. Disruptions in this process can lead to increased cytosolic pyruvate levels, promoting glycolytic metabolism often associated with cancer cell proliferation, a phenomenon known as the Warburg effect.

Through a series of experiments involving proteoliposome reconstitution, co-immunoprecipitation, and mass spectrometry, researchers confirmed the interaction between ALDH4A1 and MPC components. Functional assays demonstrated that ALDH4A1 maintains effective pyruvate transport, which in turn influences mitochondrial function and energy production. Loss of ALDH4A1 enhances cancer cell proliferation, migration, and growth in soft agar, indicating its tumor-suppressive properties.

In vivo studies using xenograft models revealed that overexpression of ALDH4A1 suppresses tumor growth, whereas its knockdown promotes rapid tumor progression. Importantly, the study showed that inhibiting the MPC complex with UK5099 disrupts ALDH4A1’s interaction with MPC, highlighting potential avenues for therapeutic targeting.

This groundbreaking discovery expands the functional repertoire of ALDH4A1 beyond proline metabolism, positioning it as an essential regulator of mitochondrial pyruvate import and cellular metabolism. Understanding and manipulating this pathway could open new strategies for cancer therapy by targeting metabolic vulnerabilities associated with the MPC complex.

Source: https://medicalxpress.com/news/2025-05-common-enzyme-role-cancer.html