Science / Target

MSDC scientists have made a breakthrough discovery of a mitochondrial protein complex they believe will change the future discovery and development of new therapeutics to treat diseases associated with age-related mitochondrial dysfunction – especially insulin sensitizers. Two papers published by two separate groups in Science have coincidentally found that two of the important proteins in the mTOT complex, which the authors renamed MPC1 and MPC2, are part of a pyruvate carrier mechanism.

MSDC researchers have defined this mitochondrial protein complex as the mitochondrial Target of Thiazolidinediones (TZDs), or mTOT, recognition complex. Thiazolidinediones are a class of drugs that improve insulin sensitivity. mTOT was located using 3H-pioglitazone (a TZD) and identified with novel photo-probes and purification. Proteins in this novel target are phylogenetically conserved, from yeast to drosophila to mouse to man. The proteins have been cloned and expressed, and bind drugs. Knockdown and metabolomics data have shown that the mTOT complex regulates pyruvate utilization and interfaces with key metabolic pathways integral to the pathophysiology of type 2 diabetes. All active TZDs bind mTOT. Of particular importance, non-TZDs also bind mTOT.

Data presented to date suggest that the mTOT protein complex functions as a molecular “sensor switch” connecting mitochondrial metabolism to important cellular activities perturbed in age-related metabolic diseases such as type 2 diabetes, including insulin sensitivity. MSDC’s novel pharmaceutical agents selectively bind and modulate proteins in the mTOT complex, effecting pyruvate utilization and resulting in improved insulin action, lipid oxidation, preservation of beta cell function, and generation of brown fat.