Mitochondrial Dysfunction in Diabetic Kidney Disease

Diabetic kidney disease (DKD) arises from chronic hyperglycaemia and is a leading cause of end-stage renal failure worldwide. Mitochondria are central to renal cell homeostasis through ATP generation, reactive oxygen species (ROS) regulation and calcium handling. In DKD, sustained high glucose and lipotoxicity impair mitochondrial biogenesis, disrupt the balance of fusion and fission and compromise the integrity of cristae—the inner membrane folds crucial for oxidative phosphorylation. Compromised electron transport chain activity exacerbates ROS overproduction, triggering oxidative damage to podocytes and tubular cells. Concurrently, defective mitophagy and selective forms of autophagy, including ER-phagy, allow the accumulation of dysfunctional organelles, fuel inflammatory and fibrotic cascades and accelerate glomerulosclerosis. Emerging evidence highlights interconnections between mitochondrial lipid remodelling, quality-control pathways and transcriptional regulators of energy metabolism. Restoring mitochondrial structure and function thus represents a promising strategy to slow DKD progression and mitigate loss of renal function.

Research from Nature Portfolio

Recent studies have elucidated key regulatory nodes in mitochondrial structure and quality control. In murine models of DKD, targeted overexpression of the complex I subunit NDUFS4 in podocytes preserved cristae morphology, optimised mitochondrial dynamics and reduced albuminuria. Super-resolution mapping identified STOML2 as a partner linking NDUFS4 to cristae-shaping machinery, supporting cristae remodelling as a therapeutic target. Separately, inhibition of thioredoxin-interacting protein (TXNIP) via a DNAzyme approach restored autophagic flux and mitophagy in tubular cells subjected to hyperglycaemia. Attenuation of TXNIP reduced mTOR pathway activation, limited extracellular matrix deposition and improved mitochondrial function, underscoring the importance of fine-tuning autophagy regulators in DKD.

Mitochondrial Dysfunction in Diabetic Kidney Disease publication trend

The graph below shows the total number of articles in mitochondrial dysfunction in diabetic kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Electron transport chain: A series of protein complexes in the inner mitochondrial membrane that transfer electrons and generate a proton gradient for ATP synthesis.

Cristae: Invaginations of the inner mitochondrial membrane that increase surface area for oxidative phosphorylation.

Cardiolipin: A unique phospholipid found in the inner mitochondrial membrane essential for membrane curvature and enzyme function.

Mitophagy: The selective autophagic removal of damaged mitochondria to maintain cellular health.

ER-phagy: The selective autophagic degradation of endoplasmic reticulum components to relieve ER stress.

References

1. NDUFS4 regulates cristae remodeling in diabetic kidney disease. Nature Communications (2024).
2. Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway. Scientific Reports (2016).
3. Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatment of diabetes and its complications: An update since 2010. Pharmacological Research (2024).
4. ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease. Cell Communication and Signaling (2024).
5. PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy. Cell Death & Disease (2023).