A model of mitochondrial O₂consumption and ATP generation in rat proximal tubule cells

Abstract

Oxygen tension in the kidney is mostly determined by O2 consumption (Qo2), which is, in turn, closely linked to tubular Na+ reabsorption. The objective of the present study was to develop a model of mitochondrial function in the proximal tubule (PT) cells of the rat renal cortex to gain more insight into the coupling between Qo2, ATP formation (GATP), ATP hydrolysis (QATP), and Na+ transport in the PT. The present model correctly predicts in vitro and in vivo measurements of Qo2, GATP, and ATP and Pi concentrations in PT cells. Our simulations suggest that O2 levels are not rate limiting in the proximal convoluted tubule, absent large metabolic perturbations. The model predicts that the rate of ATP hydrolysis and cytoplasmic pH each substantially regulate the GATP-to-Qo2 ratio, a key determinant of the number of Na+ moles actively reabsorbed per mole of O2 consumed. An isolated increase in QATP or in cytoplasmic pH raises the GATP-to-Qo2 ratio. Thus, variations in Na+ reabsorption and pH along the PT may, per se, generate axial heterogeneities in the efficiency of mitochondrial metabolism and Na+ transport. Our results also indicate that the GATP-to-Qo2 ratio is strongly impacted not only by H+ leak permeability, which reflects mitochondrial uncoupling, but also by K+ leak pathways. Simulations suggest that the negative impact of increased uncoupling in the diabetic kidney on mitochondrial metabolic efficiency is partly counterbalanced by increased rates of Na+ transport and ATP consumption. This model provides a framework to investigate the role of mitochondrial dysfunction in acute and chronic renal diseases.

A Mathematical Model of Mitochondria in Proximal Tubule and Thick Ascending Limb Cells

“…The PT accounts for two thirds of sodium reabsorption by the kidney, done mostly via active transport [51]. The work of Edwards et al [17] that we build on here suggests that the efficiency of cellular respiration in the kidney is reduced by diabetes, suggesting that could be a cause of diabetic nephropathy. Furthermore they suggest that a class of diabetes medications that target the kidney, SGLT-2 inhibitors, could worsen the nephropathic effects of diabetes.…”

“…There are three classes of question that we wish to address in this work. First, the comparative questions: a published in silico study on PT mitochondrial function has found that oxygen tension is not rate limiting in the renal cortex for ATP production [17], we compare this to the outer medulla, where lower baseline oxygen tension means that hypoxia may be more extreme. And relatedly, in line with the predictions of Zhang and Edwards [88] that ATP production should be more efficient in the mTAL, we wish to consider the ratios of ATP Synthase mediated ATP generation to Complex IV mediated oxygen consumption, i.e.…”

“…The third kind of question I’ll point to is how the PT and mTAL respectively respond to pathological circumstances, in particular to diabetes, electrolyte or pH imbalance, ischemia-reperfusion cycles, drug-use, and mitochondrial disease, along with the aforementioned hypoxia. Some of this work has been done for the PT although not all; for instance uncoupling and pH imbalance were examined in Edwards et al [17] for the PT. For this reason, this work is not just useful as an exercise in comparison, but also will break new ground in the study of the PT and the mTAL in diseased states.…”

Renal oxygenation: From data to insight

“…Thus, these models can potentially be improved by data regarding these processes, including new information being generated from models of mitochondrial function in the kidney. 99…”

“…However, these model predictions will presumably be highly influenced by the efficiency of oxygen utilization for sodium resolution in these kidneys, including how this efficiency varies locally within tissue in pathological states. Thus, these models can potentially be improved by data regarding these processes, including new information being generated from models of mitochondrial function in the kidney …”