Aging aggravated liver ischemia and reperfusion injury by promoting oxidized mtDNA mediated-macrophage pyroptosis through acetylated MCU-dependent calcium uptake

作者：Xinyi Wu, Rui Wang, Qi Zhang, Tao Liu, Junyan Liu, Xuesong Xu, Jun-Hua Gong · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02746-9 · 被引用次数：6 · 研究领域：Liver Disease and Transplantation、Organ Transplantation Techniques and Outcomes、Mitochondrial Function and Pathology

The shortage of liver donors for liver transplantation is currently an urgent problem. Elderly donors have become an important source of donor livers, but they are more prone to ischemia reperfusion injury (IRI) in liver transplantation. Therefore, exploring the effects and mechanisms of aging on liver IRI will provide a new theoretical basis for improving the survival rate of liver transplant patients. We constructed a mouse model of liver ischemia for 90 min and reperfusion for 6 or 24 h, and found that compared with young liver, the recovery of liver function in aged liver after IRI was slower. Detection of macrophage pyroptosis revealed that it was an important factor for aging deferring liver function restoration. Mechanistically, we demonstrated that aging triggered mitochondrial permeability transition pore (mPTP) channel opening to promote the release of Oxidized mtDNA (Ox-mtDNA), thereby inducing macrophage pyroptosis. Moreover, the activity of mPTP channel was mainly dependent on calcium uptake by acetylated mitochondrial calcium uniporter (MCU). These results illustrated that cytoplasmic Ox-mtDNA-induced macrophage pyroptosis was a key factor for aging exacerbating liver IRI. Calcium uptake via acetylated MCU triggered mPTP channel opening, which is an important mechanism for Ox-mtDNA release from mitochondria into the cytoplasm.