Distinct roles of PINK1 autophosphorylation in neonatal hypoxia with or without convulsions.

Abstract

This study explored the distinct roles of PINK1 in neonatal hypoxia with and without convulsions. Various models of hypoxia with different severities have been established using neonatal C57BL/6 J mice. In addition, short hairpin RNA (shRNA) interventions targeting translocase of the outer mitochondrial membrane 7 or mitochondrial ATPase associated with diverse cellular activities, such as protease 1 homolog, inhibitor, and promoter of PINK1 autophosphorylation, were administered to modulate PINK1 activity levels. After exposure to severe hypoxia (15 min) that induced convulsions, phosphorylated PINK1 levels increased, accompanied by enhanced mitophagy, increased mitochondrial reactive oxygen species, neuronal damage and elevated epileptic susceptibility. Moreover, inhibition of PINK1 phosphorylation alleviates oxidative stress injury and reduces epileptic susceptibility, whereas enhancement of PINK1 phosphorylation aggravates oxidative stress damage. PINK1-induced mitophagy and oxidative stress injury were also elevated following mild hypoxia (130 s), without convulsions. However, unlike the 15-min hypoxic condition, either increasing or suppressing PINK1 phosphorylation via shRNA intervention exacerbated hypoxia-induced injury. These findings suggest that excessive phosphorylated PINK1 levels following severe hypoxia with convulsions, promote neuronal injury and increase epileptic susceptibility. In contrast, moderate PINK1 phosphorylation, induced by mild hypoxia without convulsions, exerts neuroprotective effects. Overall, this study elucidates the dual roles of PINK1 autophosphorylation in neonatal hypoxia with and without convulsions, and provides a theoretical basis for the therapeutic modulation of PINK1 activity in neonatal hypoxia.