Control and Regulation of Substrate Selection in Cytoplasmic and Mitochondrial Catabolic Networks. A Systems Biology Analysis

Abstract

Appropriate substrate selection between fats and glucose is associated with the success of interventions that maintain health such as exercise or caloric restriction, or with the severity of diseases such as diabetes or other metabolic disorders. Although the interaction and mutual inhibition between glucose and fatty-acids (FAs) catabolism has been studied for decades, a quantitative and integrated understanding of the control and regulation of substrate selection through central catabolic pathways is lacking. We addressed this gap here using a computational model representing cardiomyocyte catabolism encompassing glucose (Glc) utilization, pyruvate transport into mitochondria and oxidation in the tricarboxylic acid (TCA) cycle, β-oxidation of palmitate (Palm), oxidative phosphorylation, ion transport, pH regulation, and ROS generation and scavenging in cytoplasmic and mitochondrial compartments. The model is described by 82 differential equations and 119 enzymatic, electron transport and substrate transport reactions accounting for regulatory mechanisms and key players, namely pyruvate dehydrogenase (PDH) and its modulation by multiple effectors. We applied metabolic control analysis to the network operating with various Glc to Palm ratios. The flux and metabolites’ concentration control were visualized through heat maps providing major insights into main control and regulatory nodes throughout the catabolic network. Metabolic pathways located in different compartments were found to reciprocally control each other. For example, glucose uptake and the ATP demand exert control on most processes in catabolism while TCA cycle activities and membrane-associated energy transduction reactions exerted control on mitochondrial processes namely β-oxidation. PFK and PDH, two highly regulated enzymes, exhibit opposite behavior from a control perspective. While PFK activity was a main rate-controlling step affecting the whole network, PDH played the role of a major regulator showing high sensitivity (elasticity) to substrate availability and key activators/inhibitors, a trait expected from a flexible substrate selector strategically located in the metabolic network. PDH regulated the rate of Glc and Palm consumption, consistent with its high sensitivity toward AcCoA, CoA, and NADH. Overall, these results indicate that the control of catabolism is highly distributed across the metabolic network suggesting that fuel selection between FAs and Glc goes well beyond the mechanisms traditionally postulated to explain the glucose-fatty-acid cycle.

Cardioprotective effect of succinate dehydrogenase inhibition in rat hearts and human myocardium with and without diabetes mellitus

“…The finding indicates that the need for higher concentration of DiMAL may be caused by factors other than protein content and complex II activity, e.g. metabolic rate control or substrate selection beyond the mechanisms traditionally claimed to explain the glucose-fatty-acid cycle 37 . Using dosages optimized to non-diabetic trabeculae, we found no protection by DiMAL in patients with diabetes.…”

Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney

“…Heart and kidneys have different energy demands, and hence, their mitochondrial OxPhos capacities and efficiencies are expected to be different [ 80 , 81 ]. However, integrated quantitative studies have not been undertaken to shed light on the reasons for the differences in the OxPhos capacities and efficiencies of these organs and tissues.…”

Targeting age‐specific changes in CD4+ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

“…Our data showed that T‐cell aging modifies mitochondrial function and glycolysis. Since changes in the metabolic pathway may also affect the selection of fuel by mitochondria, (Cortassa et al, 2019), we next dissected the energy source utilized by mitochondria in young and old naïve CD4 + T cells using a mito fuel assay.…”