Substrate Selection and Its Impact on Mitochondrial Respiration and Redox

Abstract

At the crossroad of fuels utilization, the pyruvate dehydrogenase (PDH) complex plays a key role in substrate selection (primarily of glucose and fatty acids (FAs)) by mitochondria. In mammals, substrate selection takes place in all organs although to differing degrees depending upon nutritional conditions, physiological status (e.g., feed-fast, exercise), and the absence or presence of disease (e.g., metabolic disorder, cancer). Nutritional states such as those given by starvation, diabetesdiabetes, caloric restriction, or aging can favor the oxidation of FAs over carbohydrates or vice versa, in which case modulation of the PDH complex is critically important for favoring or hindering the conservation of carbohydrate reserves. In this work, we review the literature in the context of the capacity of a cell or organ to adjust fuel selection as a function of nutrient availability and its influence on mitochondrial energetic-redox functions. We also present a computational model of PDH which includes its regulation by multiple effectors (AcCoA, CoA, NADHNADH, NAD, ATP, ADP, Ca2+, pyruvate) targeting specific kinases and phosphatases that render the enzymatic complex phosphorylated (inactive) or dephosphorylated (active), respectively. Selection by mitochondria between glucose and FAs at different relative levels of both substrates, and its impact on respiration, ROS emission, effector levels, and the fluxes through PDH and $β$-oxidation, are also presented and analyzed.