Bak Agnieszka, Hinrichs Arne, Schwaiger Anna, Fromme Tobias, Fischer Andrea, Kurome Mayuko, Zakhartchenko Valeri, Kessler Barbara, Klingenspor Martin, Wolf Eckhard, Schnieke Angelika, Fischer Konrad
Chair of Livestock Biotechnology, School of Life Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany.
Chair of Molecular Animal Breeding and Biotechnology, Ludwig-Maximillians-Universität München, 85764 Oberschleissheim, Germany.
Int J Mol Sci. 2025 Aug 11;26(16):7759. doi: 10.3390/ijms26167759.
Oxidative stress plays a central role in numerous conditions, including cancer, cardiovascular and neurodegenerative diseases, diabetes, chronic inflammation, and organ transplantation. In transplantation, oxidative stress leads to mitochondrial dysfunction, DNA and protein damage, lipid peroxidation, and activation of pro-inflammatory pathways such as NF-κB, ultimately impairing cell viability and organ function. A Kinase-Interacting Protein 1 (AKIP1) has been linked to oxidative stress regulation in transgenic mouse models. To investigate this further in a livestock setting, we generated AKIP1 transgenic pigs and assessed AKIP1's protective role against oxidative-stress-induced cell death, including apoptosis, necrosis, and ferroptosis in vitro. Our cellular analyses revealed reduced apoptosis (caspase-3/7 activity), suppressed MPTP-mediated necrosis, and decreased lipid peroxidation, suggesting protection from ferroptosis. Additionally, we observed lower mitochondrial superoxide production and enhanced mitochondrial respiration and recovery following HO-induced oxidative challenge. This is the first study to examine AKIP1 in porcine cells, providing a unique and translational platform for studying oxidative injury in a physiologically relevant species. Our in vitro data reveal that AKIP1 overexpression enhances antioxidant defenses and mitochondrial stability, offering future potential for improving graft survival in xenotransplantation.
氧化应激在众多疾病中起着核心作用，包括癌症、心血管疾病、神经退行性疾病、糖尿病、慢性炎症和器官移植。在移植过程中，氧化应激会导致线粒体功能障碍、DNA和蛋白质损伤、脂质过氧化以及促炎途径（如NF-κB）的激活，最终损害细胞活力和器官功能。在转基因小鼠模型中，一种激酶相互作用蛋白1（AKIP1）与氧化应激调节有关。为了在牲畜环境中进一步研究这一问题，我们培育了AKIP1转基因猪，并评估了AKIP1在体外对氧化应激诱导的细胞死亡（包括凋亡、坏死和铁死亡）的保护作用。我们的细胞分析显示凋亡减少（半胱天冬酶-3/7活性降低）、MPTP介导的坏死受到抑制以及脂质过氧化减少，表明对铁死亡具有保护作用。此外，我们观察到在过氧化氢诱导的氧化应激挑战后，线粒体超氧化物产生减少，线粒体呼吸和恢复增强。这是第一项在猪细胞中研究AKIP1的研究，为在生理相关物种中研究氧化损伤提供了一个独特的转化平台。我们的体外数据表明，AKIP1过表达增强了抗氧化防御和线粒体稳定性，为提高异种移植中的移植物存活率提供了未来潜力。
