Translocator Protein and Mitochondrial Dysfunction in Chronic Kidney Disease​

Dysregulation of mitochondrial homeostasis is associated with kidney tubular injury and subsequent tubulointerstitial fibrosis, contributing to the development of chronic kidney diseases (CKD). Translocator protein (TSPO), located on the outer mitochondrial membrane, is upregulated in kidney tubules after injury; however, its roles in CKD progression remain unknown.

We investigated the impact of TSPO deficiency on mitochondrial dysfunction, kidney inflammation and fibrosis in mouse models of unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (IRI). Tubule-specific TSPO-knockout mice (KspCreERT2; TSPOlox/lox) were used. The role of TSPO in metabolic energy metabolism under hypoxic stress was delineated in TSPO-deficient primary renal proximal tubular epithelial cells (RTECs) from mice and in human proximal tubular epithelial cell line (HK-2 cells). The protective effect of TSPO antagonist PK11195 treatment was evaluated in mice with CKD.

TSPO expression was increased in the proximal tubules of patients with CKD, and in UUO- and unilateral IRI-induced mice. Tubule-specific deletion of TSPO and treatment with PK11195 mitigated kidney injury, inflammation and fibrosis in UUO or unilateral IRI mice. Bulk RNA-seq analysis further revealed the enrichment of genes in metabolic pathways with increased oxidative phosphorylation (OXPHOS) and reduced glycolysis in kidneys from TSPO knockout mice. In primary RTECs subjected to hypoxic stress, deletion of TSPO preserved mitochondrial function by enhancing mitochondrial biogenesis and membrane potential, improving OXPHOS and reducing glycolysis, thereby increasing ATP production. Finally, TSPO interacted with the first enzyme of the glycolytic pathway, hexokinase 2 (HK2), on mitochondria, and TSPO knockdown triggered HK2 translocation to the cytosol, thereby decreasing its glycolytic capacity and improving mitochondrial homeostasis.

TSPO depletion protected mice from kidney injury and tubulointerstitial fibrosis during CKD progression by disrupting HK2-mediated glycolysis and enhancing mitochondrial energy metabolism.