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

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-10-07 DOI:10.1038/s41420-025-02746-9

Xin-Yi Wu, Rui Wang, Qi Zhang, Tao Liu, Jun-Yan Liu, Xue-Song Xu, Jun-Hua Gong

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引用次数: 0

Abstract

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.

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衰老通过乙酰化mcu依赖性钙摄取，促进氧化mtDNA介导的巨噬细胞热亡，加重肝脏缺血再灌注损伤。

肝移植供体短缺是目前亟待解决的问题。老年供者已成为供肝的重要来源，但他们在肝移植中更容易发生缺血再灌注损伤（IRI）。因此，探讨衰老对肝脏IRI的影响及其机制，将为提高肝移植患者的生存率提供新的理论依据。我们建立小鼠肝脏缺血90 min再灌注6、24 h模型，发现与年轻肝脏相比，老年肝脏IRI后肝功能恢复较慢。巨噬细胞焦亡检测表明，它是衰老延缓肝功能恢复的重要因素。在机制上，我们证明了衰老触发线粒体通透性过渡孔（mPTP）通道打开，促进氧化mtDNA （Ox-mtDNA）的释放，从而诱导巨噬细胞热亡。此外，mPTP通道的活性主要依赖于乙酰化线粒体单转运钙（MCU）对钙的摄取。这些结果表明，细胞质ox - mtdna诱导的巨噬细胞热亡是衰老加剧肝脏IRI的关键因素。通过乙酰化MCU的钙摄取触发mPTP通道打开，这是Ox-mtDNA从线粒体释放到细胞质的重要机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.