PCK1 loss contributes to kidney disease progression by altering mitochondrial fitness through its cataplerotic function [snRNA-seq_Human]

Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains a topic of debate. We investigate the role of PCK1, an enzyme involved in gluconeogenesis and cataplerosis, i.e. the removal of TCA intermediates from the mitochondrial matrix, in kidney disease. We demonstrate that PCK1 loss leads to injured mitochondria with decreased respiration and TCA metabolites accumulation. This results in inflammation, tubular injury and impaired tubule repair. We show that maintaining PCK1 expression in models of acute and chronic kidney disease preserves renal structure and function by improving TCA metabolite clearance. Restoration of PCK1 enhances mitochondrial health, reducing the progression to fibrosis. In humans, we confirm the correlation between PCK1 loss, mitochondrial injury as well as a failed tubule repair phenotype. We further observe the accumulation of TCA metabolites consistent with disrupted cataplerosis in chronic kidney disease. Our findings establish the maintenance of cataplerosis as an important factor of tubular physiology and repair and PCK1 as causal and potential therapeutic targets in this process. We characterized by single nucleus RNA sequencing (snRNAseq) patient kidney biopsies obtained from 6 proteinuric nephropathies