Altering mitochondrial bioenergetic efficiency

Abstract

Mitochondrial oxidative phosphorylation (OXPHOS) accounts for the vast majority of daily energy expenditure, making the efficiency at which this process occurs a potential attractive target for treating diseases associated with positive energy balance. Organic cations are a class of small carbon molecules that carry a formal charge on a nitrogen or phosphorus atom and/or contain an aliphatic amine group which protonates at physiological pH. Well studied examples from each class include the anti‐diabetic compounds berberine (+1 charge) and metformin (+2 charge at pH of 7). These compounds, like all cations, are naturally drawn to the mitochondrial matrix by the negative potential across the inner membrane. According to Nernst equilibria, the accumulation of a positively charged compound into the mitochondrial matrix is predicted to reduce the net proton motive force (Δp) available to drive ATP synthesis. In an in vitro assay of respiratory capacity, the reduced Δp will manifest as a decrease in the maximal rate at which ATP can be synthesized and therefore the maximal rate at which O2 is consumed. However, in vivo where the interplay between energetic driving forces and flux continuously adjusts to demand (e.g., ATP turnover rate), a decrease in Δp is predicted to decrease the efficiency at which those demands can be met, requiring a greater flux rate through OXPHOS and therefore energy expenditure per unit of time. Testing of >15 different organic cations in isolated mitochondria thus far has revealed remarkably similar, dose‐dependent decreases in NAD‐linked ADP‐stimulated respiration, H2O2 emission, and the Δp under different rates of clamped respiration. Additional data will be presented on the dose‐dependent impact of acute and chronic administration of organic cations in vivo in both mice and rats. Together, the data highlight a novel therapeutic model by which organic cations mitigate obesogenic conditions by altering the interplay among energetic driving forces to decrease OXPHOS efficiency. Organic cations may serve as a potential novel class of drugs for the prevention and/or treatment of diseases stemming from chronic metabolic imbalance.Support or Funding InformationNational Institutes of Health Grants R01 DK096907This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.