Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis

Abstract

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.

Mitophagy-related regulated cell death: molecular mechanisms and disease implications

“…Given the crosstalk between apoptosis and pyroptosis established by caspase-3/8, apoptosis may serve as an intermediate link between mitophagy and pyroptosis. Indeed, there have been studies revealing novel mitophagy-pyroptosis regulatory pathways, such as the caspase-3/GSDME axis and caspase-9/GSDME axis, both of which are dependent on apoptosis [ 52 , 53 ]. These discoveries suggest that other pyroptosis pathways may also be regulated by mitophagy through different mechanisms, which have been overlooked thus far.…”

Pyroptosis and inflammation‑mediated endothelial dysfunction may act as key factors in the development of erectile dysfunction (Review)

“…In addition, a review by Chen and Xu ( 39 ) reported on the ability of inflammation to stimulate the expression of caspase-1 precursors, promote the activity of caspase-1 and increase pyroptosis, and highlighted the pathological effect of caspase-1-mediated pyroptosis in vascular disease. Furthermore, androgen deprivation may cause inflammation and endothelial dysfunction via the acceleration of caspase-1 activation and induction of the pyroptosis of endothelial cells ( 31 ). Collectively, these findings may provide a novel theoretical basis for elucidating the mechanisms underlying inflammation-induced ED.…”

“…Inflammasome activation in the canonical signaling pathway may induce the release of functional caspase-1 in vivo , the activation of immune cells, and the secretion of chemokines, inflammatory factors and adhesion molecules. This exacerbates the inflammatory response, leading to severe inflammation ( 31 ). A previous study demonstrated that activation of the pyroptosis signaling pathway is associated with the development of ED ( 32 ).…”