Met-Exo attenuates mitochondrial dysfunction after hepatic ischemia-reperfusion injury in rats by modulating AMPK/SIRT1 signaling pathway

• Published in: Free radical biology & medicine 2024-03, Vol.213, p.430-442
• Main Authors: Piao, Chenxi, Wang, Yue, Lu, Xiangyu, Liu, Tao, Ma, Yajun, Li, Yuepeng, Zhang, Jiantao, Wang, Hongbin
• Format: Article
• Language: English
• Subjects: ADSCs-Exo; Hepatic ischemia reperfusion injury; Metformin; Mitochondria; Rats
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.01.049

Hepatic ischemia-reperfusion injury (IRI) results in significant postoperative liver dysfunction, and the intricate mechanism of IRI poses challenges in developing effective therapeutic drugs. Mitigating the damage caused by hepatic IRI and promoting the repair of postoperative liver injury have become focal points in recent years, holding crucial clinical significance. Adipose mesenchymal stem cell derived exosomes (ADSCs-Exo) and metformin (Met) can play a mitochondrial protective role in the treatment of hepatic IRI, but whether there is a synergistic mechanism for their intervention is not yet known. Combining the unique advantages of exosomes as drug carriers, the aim of this study was to investigate the protective effects and mechanisms of the constructed Met and ADSCs-Exo complex (Met-Exo) on the liver IRI combined with partial resection injury in rat and hypoxic reoxygenation injury of rat primary hepatocytes (HCs). In this study, firstly, we detected that mitochondrial morphology and function were severely affected in hepatic tissues after hepatic IRI combined with partial resection, and then verified by in vitro experiments that Met-Exo could promote mitochondrial biosynthesis and fusion-associated protein expression and inhibit mitochondrial fission-related protein expression by modulating the AMPK/SIRT1 signalling pathway. This indicates that ADSCs-Exo can not only play a targeting role as a drug carrier but also has a great potential to act as a vehicle to act synergistically with drugs in the treatment of tissue and organ damage, which provides a new therapeutic strategy and experimental basis for the treatment of liver injury in medical science and clinical veterinary. [Display omitted] •Hepatic IRI intricately involves mitochondrial dynamics, oxidative stress, and pro-inflammatory responses, necessitating innovative intervention strategies.•ADSCs-Exo and Met synergistically activate AMPK/SIRT1 pathways, enhancing mitochondrial function in liver injury repair.•ADSCs-Exo is a promising drug carrier for targeted effects and synergistic interactions with therapeutic agents.•Metformin, as an AMPK activator, has potential therapeutic applications in mitigating oxidative stress and apoptosis.•This research opens new therapeutic avenues for liver injuries, with implications for veterinary clinical settings.