posted on 2023-03-22, 09:43authored byWei Wang, Bo Zhao, Wenwei Gao, Wenqin Song, Jiabao Hou, Lei Zhang, Zhongyuan Xia
PTEN-induced kinase 1 (PINK1)-mediated mitophagy and
caspase-1/gasdermin
D canonical pyroptosis pathways have been implicated in the pathogenesis
of postoperative cognitive dysfunction (POCD). However, gasdermin
E (GSDME), another recently identified executioner of pyroptosis that
can be specifically cleaved by caspase-3, is highly expressed in the
brain and neurons. This study aimed to ascertain whether PINK1-dependent
mitophagy governs postoperative cognitive capacity through caspase-3/GSDME.
Twelve month old male Sprague-Dawley rats underwent exploratory laparotomy
under isoflurane anesthesia. Lipopolysaccharide (LPS)-primed SH-SY5Y
cells were used to mimic postsurgical neuroinflammation. For the interventional
study, rats were administered with adeno-associated virus serotype
9 (AAV9)-mediated silencing of Pink1 and/or caspase-3 inhibitor Ac-DEVD-CHO
(Ac-DC). SH-SY5Y cells were treated with siPINK1 and/or Ac-DC. Cognitive
performance was assessed using the Morris water maze test. The mitophagy-
and pyroptosis-related parameters were determined in the hippocampus
and SH-SY5Y cells. Anesthesia/surgery and LPS caused defective PINK1-mediated
mitophagy and activation of caspase-3/GSDME-dependent pyroptosis.
AAV-9 mediated Pink1 overexpression mitigated cognitive impairment
and caspase-3/GSDME-dependent pyroptosis. Conversely, inhibition of
PINK1 aggravates POCD and overactivates neuronal pyroptosis. These
abnormalities were rescued by Ac-DC treatment. Collectively, PINK1-mediated
mitophagy regulates anesthesia and surgery-induced cognitive impairment
by negatively affecting the caspase-3/GSDME pyroptosis pathway, which
provides a promising therapeutic target for POCD.