PTEN modulates mitochondrial dysfunction in podocytes via the PINK1/Parkin signal pathway

Mitochondrial dysfunction and impaired autophagy in podocytes contribute to the pathogenesis of kidney diseases, and the phosphatase and tensin homolog (PTEN)-PTEN-induced putative kinase 1 (PINK1)/Parkin signaling axis has emerged as a critical regulator of mitochondrial quality control and podocyte survival; however, the precise underlying mechanisms remain unclear. This study investigates how the PTEN-PINK1/Parkin axis governs mitochondrial quality control in podocytes.

In vitro podocyte models with PTEN gene overexpression and silencing were developed to assess changes in podocyte mitochondrial function. Podocyte apoptosis was quantified using an apoptosis detection kit, while mitochondrial membrane potential alterations were measured with the JC-1 Mitochondrial Membrane Potential Detection Kit across all experimental groups. Immunofluorescence and Western blot were used to evaluate the expression and distribution of mitophagy-related proteins, while transmission electron microscopy was employed to observe mitochondrial autophagosomes.

PTEN depletion markedly suppressed PINK1 accumulation, leading to attenuated Parkin recruitment and LC3-I to LC3-II conversion. This defect correlated with defective clearance of depolarized mitochondria and exacerbated organelle damage. Conversely, PTEN upregulation potentiated PINK1 stabilization, enhanced Parkin translocation to mitochondria, and promoted LC3-II-mediated autophagosome formation, collectively restoring mitophagic autophagosome formation.

Podocyte-specific PTEN overexpression confers protection against glomerular podocyte injury by mitigating mitophagy dysfunction via the PTEN-PINK1/Parkin signal pathway, highlighting a potential therapeutic target for glomerular diseases.