Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, China.
Shock. 2024 Aug 1;62(2):235-244. doi: 10.1097/SHK.0000000000002392. Epub 2024 May 15.
Sepsis-induced acute kidney injury (SAKI) poses a significant clinical challenge with high morbidity and mortality. Excessive mitochondrial fission has been identified as the central pathogenesis of sepsis-associated organ damage, which is also implicated in the early stages of SAKI. Sirtuin 5 (SIRT5) has emerged as a central regulator of cellular mitochondrial function; however, its role in the regulation of sepsis-induced excessive mitochondrial fission in kidney and the underlying mechanism remains unclear. In this study, SAKI was modeled in mice through cecal ligation and puncture, and in human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide (LPS), to mimic the cell SAKI model. Our findings revealed that septic mice with a SIRT5 knockout exhibited shortened survival times and elevated levels of renal injury compared to wild-type mice, suggesting the significant involvement of SIRT5 in SAKI pathophysiology. Additionally, we observed that SIRT5 depletion led to increased renal mitochondrial fission, while the use of a mitochondrial fission inhibitor (Mdivi-1) reversed the detrimental effects caused by SIRT5 depletion, emphasizing the pivotal role of SIRT5 in preventing excessive mitochondrial fission. In vitro experiments demonstrated that the overexpression of SIRT5 effectively mitigated the adverse effects of LPS on HK-2 cells viability and mitochondrial fission. Conversely, downregulation of SIRT5 decreased HK-2 cells viability and exacerbated LPS-induced mitochondrial fission. Mechanistically, the protective function of SIRT5 may be in part, ascribed to its desuccinylating action on ATPase inhibitory factor 1. In conclusion, this study provides novel insights into the underlying mechanisms of SAKI, suggesting the possibility of identifying future drug targets in terms of improved mitochondrial dynamics by SIRT5.
脓毒症诱导的急性肾损伤（SAKI）具有很高的发病率和死亡率，是一个重大的临床挑战。过多的线粒体裂变已被确定为与脓毒症相关的器官损伤的中心发病机制，这也与 SAKI 的早期阶段有关。Sirtuin 5（SIRT5）已成为细胞线粒体功能的中央调节因子；然而，其在调节肾脏中脓毒症诱导的过多线粒体裂变中的作用及其潜在机制尚不清楚。在这项研究中，通过盲肠结扎和穿刺在小鼠中建立 SAKI 模型，并在脂多糖（LPS）刺激的人肾小管上皮（HK-2）细胞中模拟细胞 SAKI 模型。我们的研究结果表明，与野生型小鼠相比，SIRT5 敲除的脓毒症小鼠的存活时间缩短，肾脏损伤水平升高，这表明 SIRT5 显著参与了 SAKI 的病理生理学过程。此外，我们观察到 SIRT5 耗竭导致肾脏线粒体裂变增加，而使用线粒体裂变抑制剂（Mdivi-1）则逆转了 SIRT5 耗竭引起的有害作用，强调了 SIRT5 在防止过度线粒体裂变中的关键作用。体外实验表明，SIRT5 的过表达可有效减轻 LPS 对 HK-2 细胞活力和线粒体裂变的不良影响。相反，SIRT5 的下调降低了 HK-2 细胞的活力，并加剧了 LPS 诱导的线粒体裂变。从机制上讲，SIRT5 的保护作用部分归因于其对 ATPase 抑制因子 1 的脱琥珀酰基作用。总之，这项研究为 SAKI 的潜在机制提供了新的见解，表明通过 SIRT5 可以确定未来药物靶点，以改善线粒体动力学。
