Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan

Abstract

As a nodal mediator of pyruvate metabolism, the mitochondrial pyruvate carrier (MPC) plays a pivotal role in many physiological and pathological processes across the human lifespan, from embryonic development to aging-associated neurodegeneration. Emerging research highlights the importance of the MPC in diverse conditions, such as immune cell activation, cancer cell stemness, and dopamine production in Parkinson’s disease models. Whether MPC function ameliorates or contributes to disease is highly specific to tissue and cell type. Cell- and tissue-specific differences in MPC content and activity suggest that MPC function is tightly regulated as a mechanism of metabolic, cellular, and organismal control. Accordingly, recent studies on cancer and diabetes have identified protein–protein interactions, post-translational processes, and transcriptional factors that modulate MPC function. This growing body of literature demonstrates that the MPC and other mitochondrial carriers comprise a versatile and dynamic network undergirding the metabolism of health and disease.

Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD

“…This effect is mediated by the decreased amount of pyruvate metabolized to acetyl-CoA and the decreased mitochondrial ROS production (42). Even though we do not have evidence of the mechanism, we speculate that the observed gene-by-Mastiha interaction could be mediated through transcription factors, protein interactions or post-transcriptional modifications (41).…”

“…The same allele has been associated with lower expression of the MPC1 (Mitochondrial Pyruvate Carrier-1) gene in whole blood (36,39,40). The MPC1 gene encodes a protein, part of the MPC1/MPC2 heterodimer, responsible for transporting pyruvate from the cytoplasm into mitochondria (41). While downregulation of the MPC1 expression seems to be detrimental for several forms of cancer, NASH/NAFLD phenotypes seem to benefit by the MPC disruption (41,42).…”

“…The MPC1 gene encodes a protein, part of the MPC1/MPC2 heterodimer, responsible for transporting pyruvate from the cytoplasm into mitochondria (41). While downregulation of the MPC1 expression seems to be detrimental for several forms of cancer, NASH/NAFLD phenotypes seem to benefit by the MPC disruption (41,42). This effect is mediated by the decreased amount of pyruvate metabolized to acetyl-CoA and the decreased mitochondrial ROS production (42).…”

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

“…MPC is located in the mitochondrial inner membrane and is responsible for importing pyruvate, the end-product of glycolysis, from the cytosol to the mitochondrial matrix. MPC is Janus-faced regarding cancer progression [ 8 , 9 , 10 ]. Some cancers exhibit partial to complete loss of MPC expression that is associated with increased cell proliferation and stem cell marker expression [ 9 , 11 ].…”

Insights on the Quest for the Structure–Function Relationship of the Mitochondrial Pyruvate Carrier

“…Two systematic reviews of the vast physiology and clinical importance of MPC were recently presented [ 15 , 16 ]. Albeit briefly, the current knowledge on the structure of MPC—which remains mostly hypothetical owing to underlying technical difficulties—was also examined.…”