Yuan Yi, Wang Xiaoqian, Cui Yaru, Zhou Hua, Li Wenna, Teng Qian, Wang Hongjin, Sun Bohan, Wang Qiaoyun, Sun Hongliu, Tang Jianhua
School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China.
Affiliated Yantai Mountain Hospital, Binzhou Medical University, Yantai, 264003, China.
Sci Rep. 2025 Apr 29;15(1):15078. doi: 10.1038/s41598-025-99915-8.
This study investigated the roles and mechanisms of PINK1 activity in neonatal hypoxia-induced seizures with shRNA intervention targeting translocase outer mitochondrial membrane 7 (TOM7), the positive regulator of PINK1 autophosphorylation, or overlapping with the m-AAA protease 1 homolog (OMA1), the negative regulator of PINK1 autophosphorylation. Studies have suggested that in hypoxia-induced neonatal seizures, the phosphorylation level of PINK1 is significantly increased and the mitophagic pathway is activated, accompanied by neuronal damage and learning-memory deficits. Inhibiting PINK1 phosphorylation by reducing TOM7 expression alleviated mitophagy, mitochondrial oxidative stress, neuronal damage and seizures. In contrast, the inhibition of OMA1 expression resulted in a further increase in PINK1 phosphorylation and aggravated hypoxia-induced seizures and neuronal injury. This study implicated PINK1 activity in neonatal hypoxia and suggest that attenuated PINK1 autophosphorylation may have neuroprotective and anti-seizure effects in neonatal hypoxia.
本研究通过针对线粒体外膜转位酶7（TOM7，PINK1自磷酸化的正向调节因子）或与m-AAA蛋白酶1同源物（OMA1，PINK1自磷酸化的负向调节因子）重叠区域进行shRNA干预，研究了PINK1活性在新生儿缺氧诱导惊厥中的作用及机制。研究表明，在缺氧诱导的新生儿惊厥中，PINK1的磷酸化水平显著升高，线粒体自噬途径被激活，同时伴有神经元损伤和学习记忆缺陷。通过降低TOM7表达抑制PINK1磷酸化可减轻线粒体自噬、线粒体氧化应激、神经元损伤和惊厥。相反，抑制OMA1表达导致PINK1磷酸化进一步增加，并加重缺氧诱导的惊厥和神经元损伤。本研究表明PINK1活性与新生儿缺氧有关，并提示减弱PINK1自磷酸化可能对新生儿缺氧具有神经保护和抗惊厥作用。
