HSDL2 regulates mitochondrial dynamics and mitophagy to protect against diabetic peripheral neuropathy

We sought to elucidate the role of HSDL2 in Schwann cell mitochondrial quality control in diabetic peripheral neuropathy (DPN), determine its effects on high-glucose-induced cellular injury and DPN progression, and investigate its association with mitochondrial dynamics and PINK1/Parkin-associated mitophagy.

HSDL2 was upregulated in Schwann cells under diabetic stress. HSDL2 knockdown reduced the levels of mitophagy-related proteins and LC3B-mitochondria colocalization, accompanied by increased ROS accumulation, ATP depletion, and apoptosis. HSDL2 overexpression produced the opposite effects, and its protective effects were partially attenuated by 3-methyladenine treatment. HSDL2 manipulation also altered mitochondrial morphology and the phosphorylation of DRP1 at Ser616 and Ser637, consistent with changes in DRP1-associated mitochondrial dynamics. AAV-mediated HSDL2 overexpression alleviated sensory dysfunction and sciatic nerve pathology in db/db mice.

These findings support a protective role for HSDL2 under hyperglycaemic stress, with changes in mitochondrial dynamics and PINK1/Parkin-associated mitophagy potentially contributing to its protective effects. Further studies are needed to determine whether HSDL2 may serve as a therapeutic target for DPN.