Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation.

IF 5.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Redox Report Pub Date : 2024-12-01 Epub Date: 2024-02-08 DOI:10.1080/13510002.2024.2312320
Yongjun Yang, Qian Chen, Shijun Fan, Yongling Lu, Qianyin Huang, Xin Liu, Xi Peng
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Abstract

Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.

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谷氨酰胺通过 SIRT4 依赖性蛋白去乙酰化促进线粒体 HSP60-HSP10 复合物的组装,从而维持能量代谢并减轻烧伤败血症对肝脏的损伤。
烧伤和烧伤败血症的特点是持续和严重的高分解代谢,会导致能量代谢功能障碍,从而加重器官损伤和全身性疾病。谷氨酰胺(Gln)是一种关键营养素,能显著补充烧伤和脓毒症患者的能量代谢,但其在底物供应之外的确切作用尚不清楚。在这项研究中,我们证实 Gln 可通过维持能量供应和恢复氧化还原平衡来缓解肝损伤。同时,Gln 还能挽救功能失调的线粒体电子传递链(ETC)复合物,改善 ATP 生成,减少氧化应激,保护肝细胞免受烧伤脓毒症损伤。从机理上讲,我们发现 Gln 可通过上调 SIRT4 的蛋白质合成和提高维持 SIRT4 活性的辅酶烟酰胺腺嘌呤二核苷酸(NAD+)的水平来激活 SIRT4。这反过来又减少了休克蛋白(HSP)60 的乙酰化,促进了 HSP60-HSP10 复合物的组装,而 HSP60-HSP10 复合物可维持 ETC 复合物 II 和 III 的活性,从而维持 ATP 的生成并减少活性氧的释放。总之,我们的研究发现了一种以前未知的药理机制,涉及对 HSP60-HSP10 组装的调节,通过这种机制,Gln 可以恢复线粒体复合物的活性,维持细胞能量代谢,并在烧伤败血症中发挥保护肝脏的作用。
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来源期刊
Redox Report
Redox Report 生物-生化与分子生物学
CiteScore
6.10
自引率
0.00%
发文量
28
审稿时长
>12 weeks
期刊介绍: Redox Report is a multidisciplinary peer-reviewed open access journal focusing on the role of free radicals, oxidative stress, activated oxygen, perioxidative and redox processes, primarily in the human environment and human pathology. Relevant papers on the animal and plant environment, biology and pathology will also be included. While emphasis is placed upon methodological and intellectual advances underpinned by new data, the journal offers scope for review, hypotheses, critiques and other forms of discussion.
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