Quercetin inhibits necroptosis in cardiomyocytes after ischemia–reperfusion via DNA‐PKcs‐SIRT5‐orchestrated mitochondrial quality control

Abstract

We investigated the mechanism by which quercetin preserves mitochondrial quality control (MQC) in cardiomyocytes subjected to ischemia–reperfusion stress. An enzyme‐linked immunosorbent assay was employed in the in vivo experiments to assess myocardial injury markers, measure the transcript levels of SIRT5/DNAPK‐cs/MLKL during various time intervals of ischemia–reperfusion, and observe structural changes in cardiomyocytes using transmission electron microscopy. In in vitro investigations, adenovirus transfection was employed to establish a gene‐modified model of DNA‐PKcs, and primary cardiomyocytes were obtained from a mouse model with modified SIRT5 gene. Reverse transcription polymerase chain reaction, laser confocal microscopy, immunofluorescence localization, JC‐1 fluorescence assay, Seahorse energy analysis, and various other assays were applied to corroborate the regulatory influence of quercetin on the MQC network in cardiomyocytes after ischemia–reperfusion. In vitro experiments demonstrated that ischemia–reperfusion injury caused changes in the structure of the myocardium. It was seen that quercetin had a beneficial effect on the myocardial tissue, providing protection. As the ischemia–reperfusion process continued, the levels of DNA‐PKcs/SIRT5/MLKL transcripts were also found to change. In vitro investigations revealed that quercetin mitigated cardiomyocyte injury caused by mitochondrial oxidative stress through DNA‐PKcs, and regulated mitophagy and mitochondrial kinetics to sustain optimal mitochondrial energy metabolism levels. Quercetin, through SIRT5 desuccinylation, modulated the stability of DNA‐PKcs, and together they regulated the “mitophagy‐unfolded protein response.” This preserved the integrity of mitochondrial membrane and genome, mitochondrial dynamics, and mitochondrial energy metabolism. Quercetin may operate synergistically to oversee the regulation of mitophagy and the unfolded protein response through DNA‐PKcs‐SIRT5 interaction.

Cardiovascular protection of YiyiFuzi powder and the potential mechanisms through modulating mitochondria-endoplasmic reticulum interactions

“…This autonomic system safeguards cardiomyocytes during stress responses by inhibiting mitochondrial apoptosis, mitochondrial-related ER stress, and the mitochondrial-related unfolded protein response (UPR). As a result, it mitigates ischemia and hypoxia injuries in sinoatrial node cells ( Chang et al, 2023a ; Chang et al, 2024b ) and normal cardiomyocytes ( Chang et al, 2021 ; Chang et al, 2022 ; Chang et al, 2023b ; Chang et al, 2024a ), ultimately protecting cardiovascular health. It is evident that the roles of mitochondria and ER in cardiovascular health are intertwined, indicating an interconnected relationship rather than independent functions.…”