Phosphoenolpyruvate carboxykinase 1-mediated cataplerosis is required to maintain mitochondrial fitness and to avoid kidney disease progression.

Abstract

INTRODUCTION Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains debatable. Here, we investigate the role of phosphoenolpyruvate carboxykinase 1 (PCK1), an enzyme involved in gluconeogenesis and cataplerosis (removal of tricarboxylic acid (TCA) cycle intermediates from the mitochondrial matrix) in kidney disease progression. METHODS We used mice with kidney tubular cell-specific deletion or overexpression of the PCK1 enzyme, and different models of kidney injury such as ischemia-reperfusion injury or cis-platin-induced nephropathy. Furthermore, we measured metabolites in kidney biopsy tissue from patients with stage 3b/4 chronic kidney disease (CKD). RESULTS Using flux analysis, we confirm that cataplerosis and the TCA cycle are blocked by PCK1 deficiency. This results in injured mitochondria leading to inflammation, tubular injury and impaired tubular cell repair. Inversely, maintaining PCK1 function in different models of kidney injury preserves kidney structure, improves TCA cycle metabolite clearance and increase ATP production. In kidney biopsies from different patient cohorts, we confirm the correlation between PCK1 loss, mitochondrial injury and a failed tubular cell repair phenotype. Furthermore, in CKD, accumulation of TCA cycle metabolites is consistent with disrupted cataplerosis. CONCLUSIONS Overall, we demonstrate that PCK1 loss in kidney tubular cells leads to decreased respiration and the accumulation of TCA cycle metabolites. Maintenance of cataplerosis is an important factor of tubular physiology and repair, with PCK1 serving as a causal and potential therapeutic target in this process. PCK1 restoration enhances mitochondrial health, limiting progression to inflammation and fibrosis.