Department of Pharmacology, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China; Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
Department of Pharmacology, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China; Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167527. doi: 10.1016/j.bbadis.2024.167527. Epub 2024 Sep 26.
Mitochondrial dynamics plays a crucial role in the occurrence and development of non-alcoholic fatty liver diseases (NAFLD). SENP1, a SUMO-specific protease, catalyzes protein de-SUMOylation and involves in various physiological and pathological processes. However, the exact role of SENP1 in NAFLD remains unclear. Therefore, we investigated the regulatory role of SENP1 in mitochondrial dynamics during the progression of NAFLD. In the study, the NAFLD in vivo model induced by high fat diet (HFD) and in vitro model induced by free fatty acids (FFA) were established to investigate the role and underlying mechanism of SENP1 through detecting mitochondrial morphology and dynamics. Our results showed that the down-regulation of SENP1 expression and the mitochondrial dynamics dysregulation occurred in the NAFLD, evidenced as mitochondrial fragmentation, up-regulation of p-Drp1 ser616 and down-regulation of MFN2, OPA1. However, over-expression of SENP1 significantly alleviated the NAFLD, rectified the mitochondrial dynamics disorder, reduced Cyt-c release and ROS levels induced by FFA or HFD; moreover, the over-expression of SENP1 also reduced the SUMOylation levels of Drp1 and prevented the Drp1 translocation to mitochondria. Our findings suggest that the possible mechanisms of SENP1 were through rectifying the mitochondrial dynamics disorder, reducing Cyt-c release and ROS-mediated oxidative stress. The findings would provide a novel target for the prevention and treatment of NALFD.
线粒体动力学在非酒精性脂肪性肝病（NAFLD）的发生和发展中起着至关重要的作用。SUMO 特异性蛋白酶 SENP1 催化蛋白去 SUMO 化，并参与各种生理和病理过程。然而，SENP1 在 NAFLD 中的确切作用尚不清楚。因此，我们研究了 SENP1 在 NAFLD 进展过程中线粒体动力学的调节作用。在该研究中，通过高脂肪饮食（HFD）建立了体内 NAFLD 模型，通过游离脂肪酸（FFA）建立了体外模型，通过检测线粒体形态和动力学来研究 SENP1 的作用及其潜在机制。我们的结果表明，在 NAFLD 中发生了 SENP1 表达下调和线粒体动力学失调，表现为线粒体碎片化、p-Drp1ser616 上调和 MFN2、OPA1 下调。然而，SENP1 的过表达显著缓解了 NAFLD，纠正了线粒体动力学紊乱，减少了 FFA 或 HFD 诱导的 Cyt-c 释放和 ROS 水平；此外，SENP1 的过表达还降低了 Drp1 的 SUMO 化水平，并阻止了 Drp1 向线粒体的易位。我们的研究结果表明，SENP1 的可能机制是通过纠正线粒体动力学紊乱、减少 Cyt-c 释放和 ROS 介导的氧化应激。这些发现为预防和治疗 NALFD 提供了一个新的靶点。
