mitochondrial uncouplers

Mitochondrial uncouplers (MU) are small molecules that are capable of transporting protons from the mitochondrial inner membrane back to the matrix independent of ATP Synthase, the enzyme responsible for catalyzing the synthesis of ATP from ADP and Pi. Therefore, MUs can indirectly lower ATP generation from excessive nutrient intake. In other words, MUs can increase nutrient oxidation and inefficient energy production in form of heat which leads to bodily compensation through the burning of fat. Furthermore, one observed positive side effect is a significant decrease in the production of reactive oxygen species (ROS).

Excessive nutrition intake inevitably leads to metabolic-related problems such as obesity and type-2 diabetes. Increased fat buildup within liver cells progresses into a form of steatosis (cell enlargement) called NAFLD (non-alcoholic fatty liver disease), as well as a type of steatohepatitis (inflammation and cell damage) called NASH (non-alcoholic steatohepatitis). Eventually, these will result in cirrhosis (fibrosis, organ failure) and death. NAFLD affects one out of every four people in western countries and is a major part of metabolic syndrome (high blood sugar, cholesterol, increased blood pressure, and body fat).

The world’s most famous MU is 2,4-dinitrophenol (DNP) which has significant weight loss results but unfortunately is accompanied by adverse side effects such as the polarization of the mitochondrial cellular membrane. Additionally, DNP also possesses a narrow therapeutic window and treatment often results in serious cell damage and death. Efforts to prepare non-polarizing analogs of DNP have been made with the goal of these novel molecules to act as alternative MUs.[1] For example, the molecule BAM15, presented by prof. Santos and co-workers, has better uncoupling properties compared to DNP and effectively prevents and reverses obesity without affecting food intake or lean mass. Nevertheless, BAM15 still has limitations, for example, short metabolic half-life and poor water solubility which can be improved.[2] 


[1]      a) Chen, S.-Y., M. Beretta, S. J. Alexopoulos, D. P. Shah, E. M. Olzomer, S. R. Hargett, E. S. Childress, J. M. Salamoun, I. Aleksovska, A. Roseblade, C. Cranfield, T. Rawling, K. G. R. Quinlan, M. J. Morris, S. P. Tucker, W. L. Santos, K. L. Hoehn, Metab. Clin. Exp. 2021, 117; b) Childress, E. S., J. M. Salamoun, S. R. Hargett, S. J. Alexopoulos, S.-Y. Chen, D. P. Shah, J. Santiago-Rivera, C. J. Garcia, Y. Dai, S. P. Tucker, K. L. Hoehn, W. L. Santos, J. Med. Chem. 2020, 63, 2511; c) Murray, J. H., S. Hargett, K. L. Hoehn, W. L. Santos, Bioorganic Med. Chem. Let. 2020, 30, 127057; d) Salamoun, J. M., C. J. Garcia, S. R. Hargett, J. H. Murray, S.-Y. Chen, M. Beretta, S. J. Alexopoulos, D. P. Shah, E. M. Olzomer, S. P. Tucker, K. L. Hoehn, W. L. Santos, J. Med. Chem. 2020, 63, 6203; e) Childress, E. S., S. J. Alexopoulos, K. L. Hoehn, W. L. Santos, J. Med. Chem. 2018, 61, 4641; f) Kenwood, B. M., J. L. Weaver, A. Bajwa, I. K. Poon, F. L. Byrne, B. A. Murrow, J. A. Calderone, L. Huang, A. S. Divakaruni, J. L. Tomsig, K. Okabe, R. H. Lo, G. Cameron Coleman, L. Columbus, Z. Yan, J. J. Saucerman, J. S. Smith, J. W. Holmes, K. R. Lynch, K. S. Ravichandran, S. Uchiyama, W. L. Santos, G. W. Rogers, M. D. Okusa, D. A. Bayliss, K. L. Hoehn, Mol. Metab. 2014, 3, 114.

[2]      Alexopoulos, S. J., S.-Y. Chen, A. E. Brandon, J. M. Salamoun, F. L. Byrne, C. J. Garcia, M. Beretta, E. M. Olzomer, D. P. Shah, A. M. Philp, S. R. Hargett, R. T. Lawrence, B. Lee, J. Sligar, P. Carrive, S. P. Tucker, A. Philp, C. Lackner, N. Turner, G. J. Cooney, W. L. Santos, K. L. Hoehn, Nat. Commun. 2020, 11, 2397.