Mitochondrial Pyruvate Carrier: A Gateway to Future Metabolic Therapies
Structural and mechanistic insights unveil MPC as a strategic target in cancer, liver disease, and mitochondrial medicine. World Mitochondria Society 2025 Copyright
Fifty years after the mitochondrial pyruvate carrier (MPC) was first identified, researchers have now resolved its molecular structure and mechanism of action. In a landmark study published in Science Advances, Sichrovsky et al. (2025) unveiled how this critical mitochondrial complex mediates pyruvate transport and how its inhibition could be leveraged for therapeutic purposes in cancer, metabolic disorders, and more.
What Is the MPC and Why Is It Important?
The mitochondrial pyruvate carrier (MPC) is a protein complex located in the inner mitochondrial membrane. It enables the import of pyruvate, a central metabolite derived from glycolysis, into mitochondria where it fuels the TCA cycle and ATP production. This process is fundamental to energy metabolism, redox regulation, and biosynthesis.
Until now, the exact structure and working mechanism of the MPC had remained elusive, limiting our ability to design targeted drugs.
Major Discoveries of the Study by Prof. Edmund Kunji and his teams
Molecular Structure of MPC:
The authors used cryo-electron microscopy to capture the architecture of the human MPC complex. They discovered that MPC forms a heterodimeric transport unit (MPC1/MPC2), creating a selective channel that guides pyruvate across the inner mitochondrial membrane.
Mechanism of Transport and Inhibition:
The study revealed how small-molecule inhibitors bind to the MPC complex and block its function, offering a blueprint for drug development. Structural analysis pinpointed specific binding sites that explain both transport dynamics and inhibition sensitivity.
Conserved Functionality:
Evolutionary conservation of the MPC mechanism across species (including yeast and human) underscores its universal biological role in cellular energy homeostasis.
Therapeutic Implications
Cancer:
Some tumors overexpress MPC to fuel high mitochondrial activity. MPC inhibitors could starve these cells of essential metabolites, selectively disrupting their growth.
Metabolic Diseases:
In conditions like non-alcoholic fatty liver disease (NAFLD), blocking MPC forces hepatocytes to burn fat instead of relying on glucose, leading to reduced liver fat accumulation.
Regenerative Medicine & Hair Growth:
MPC inhibition has been shown to stimulate lactate production, which may promote hair follicle cell activation, opening potential new treatments for alopecia.
Mitochondrial Dysfunction & Neurodegeneration:
Targeting MPC may allow modulation of energy metabolism in neurodegenerative and mitochondrial diseases, where ATP production and redox balance are impaired.
Broader Impact
Drug Development:
The structural elucidation of MPC provides a molecular framework for designing selective modulators, setting the stage for new classes of metabolic drugs.
Precision Medicine:
Understanding individual differences in MPC structure/function may lead to personalized metabolic therapies tailored to genetic or disease-specific metabolic profiles.
Synthetic Biology & Bioenergetics:
The detailed MPC model can inform the engineering of customized metabolic pathways, supporting advances in synthetic biology, cell therapies, and biotechnology.
Statement of Prof. Marvin Edeas and Prof. Volkmar Weissig, chairman of World Mitochondria Society, "The study by Sichrovsky et al. marks a strategic breakthrough in the field of mitochondrial biology and cellular metabolism. By revealing the detailed structure and transport mechanism of the mitochondrial pyruvate carrier (MPC), the researchers have clarified how a key metabolic gatekeeper functions at the molecular level. This discovery is important because it gives scientists the precise blueprint needed to design drugs that selectively modulate mitochondrial metabolism. Such interventions could target cancer cells that rely on mitochondrial energy, help treat liver conditions by shifting how cells use nutrients, and even promote regeneration in other tissues."
Overall, this work transforms the MPC from a poorly understood protein into a strategic therapeutic target. It opens new possibilities for developing mitochondria-targeted treatments that are safer, more effective, and tailored to the metabolic needs of each disease.
Prof. Edmund Kunji from the University of Cambridge will give a major talk entitled Targeting mitochondrial pyruvate carrier: impact on future metabolic therapies, during the Targeting Mitochondria 2025 Congress, which will be held on October 22-24, in Berlin Germany.
Reference:
Sichrovsky, M., Lacabanne, D., Ruprecht, J.J., Rana, J.J., et al. (2025). Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier. Science Advances, 18 April 2025. DOI: 10.1126/sciadv.adw1489
