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 (G_ATP), ATP hydrolysis (Q_ATP), and Na⁺ transport in the PT. The present model correctly predicts in vitro and in vivo measurements of Qo₂, G_ATP, and ATP and P_i 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 G_ATP-to-Qo₂ ratio, a key determinant of the number of Na⁺ moles actively reabsorbed per mole of O₂ consumed. An isolated increase in Q_ATP or in cytoplasmic pH raises the G_ATP-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 G_ATP-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.