XIAP-ULK1 Axis Controls Mitophagy and Carnitine Balance in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is one of the most prevalent and serious complications of diabetes, affecting roughly one-third of diabetic patients and representing a leading cause of end-stage renal disease worldwide. Mitochondrial dysfunction and impaired quality-control pathways are increasingly recognized as central drivers of renal tubular injury in DKD, yet the specific molecular mechanisms linking mitophagy failure to metabolic disruption in the kidney have remained poorly defined.

This study systematically investigated how the E3 ubiquitin ligase XIAP (X-linked inhibitor of apoptosis) regulates ULK1 (unc-51 like autophagy activating kinase 1), the primary kinase that initiates mitophagy. Using renal biopsy samples from DKD patients, streptozotocin (STZ)-induced diabetic mouse models, high-glucose (HG)-treated proximal tubular epithelial cells (TECs), and molecular docking analyses, the authors found that XIAP is significantly upregulated in DKD kidneys. Elevated XIAP drives proteasomal degradation of ULK1 through K48-linked polyubiquitination, effectively shutting down mitophagy and allowing dysfunctional mitochondria to accumulate in tubular cells.

RNA sequencing and single-cell RNA sequencing (scRNA-seq) analyses of DKD tissue revealed that carnitine metabolism—essential for shuttling long-chain fatty acids into mitochondria for beta-oxidation—was among the most significantly disrupted metabolic pathways. Key enzymes including TMLHE (trimethyllysine hydroxylase, epsilon) were downregulated, and LC-MS-based metabolomics confirmed reduced carnitine levels in diabetic kidneys. Impaired mitophagy and mitochondrial dysfunction were mechanistically linked to these carnitine deficits, creating a reinforcing cycle of metabolic and mitochondrial deterioration.

To restore the pathway, the researchers employed two complementary strategies. First, echinacoside—a natural phenylethanoid glycoside identified via molecular docking as a ULK1 agonist—was shown to stabilize ULK1 and rescue mitophagy flux, as confirmed by CETSA and DARTS binding assays. Second, L-carnitine supplementation directly replenished carnitine pools. Both interventions, individually and in combination, improved mitochondrial morphology (assessed by TEM), reduced oxidative stress, lowered markers of kidney injury (serum creatinine, BUN, ACR), and attenuated renal fibrosis and tubular damage in diabetic mice. AAV-mediated tubule-specific ULK1 overexpression produced similar protective effects, further validating the axis.

These findings position the XIAP-ULK1-mitophagy-carnitine axis as a coherent and therapeutically actionable pathway in DKD. The dual approach of restoring mitophagy and replenishing metabolic substrates may offer greater efficacy than either strategy alone, and the natural compound echinacoside represents a readily translatable ULK1-targeting agent worthy of further clinical investigation.