SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain.
SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain.
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DOI：
10.1038/s41598-018-35890-7
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发表时间：
2018-12-03
影响因子：
4.6
通讯作者：
Pugazhenthi S
中科院分区：
文献类型：
--
作者：
Tyagi A;Nguyen CU;Chong T;Michel CR;Fritz KS;Reisdorph N;Knaub L;Reusch JEB;Pugazhenthi S
SIRT3是线粒体主要的脱乙酰酶，在增强线粒体蛋白质的功能方面发挥着重要作用。SIRT3的下调是代谢综合征的关键组成部分，代谢综合征是肥胖、糖尿病和心血管疾病的先决条件。在这项研究中，我们研究了西方饮食喂养的代谢综合征模型SIRT3−/−小鼠脑线粒体蛋白超乙酰化的影响。在西方饮食喂养和SIRT3缺失后，脑线粒体蛋白被高乙酰化。为了鉴定这些高乙酰化蛋白质，我们用无标记串联质谱仪进行了全面的乙酰化组分析。基因本体论途径分析揭示了SIRT3缺失介导的几种代谢途径中的酶的下调，包括脂肪酸氧化和三羧酸循环。线粒体呼吸在多种状态下受损，线粒体分裂蛋白Mfn1和Mfn2水平降低。原天冬氨酸氨基转移酶-1裂解提示有炎性小体形成。近距离连接实验检测炎性小体与caspase-1和NLRP3的组装。神经炎症指标包括小胶质细胞增多症和脑IL-1β表达升高。重要的是，当喂食卡路里丰富的西方饮食时，这些发现在sirt3−/−小鼠身上进一步恶化。本研究的观察结果提示，SIRT3缺乏所致的脑线粒体功能障碍和代谢综合征的神经炎症可能在老年认知功能减退中起作用。
SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3−/− mice, a model for metabolic syndrome. Brain mitochondrial proteins were hyperacetylated, following western diet feeding and Sirt3 deletion. To identity these hyperacetylated proteins, we performed a comprehensive acetylome analysis by label-free tandem mass spectrometry. Gene ontology pathway analysis revealed Sirt3 deletion-mediated downregulation of enzymes in several metabolic pathways, including fatty acid oxidation and tricarboxylic acid cycle. Mitochondrial respiration was impaired at multiple states, along with lower levels of mitochondrial fission proteins Mfn1 and Mfn2. Cleavage of procaspase-1 suggested inflammasome formation. Assembly of inflammasomes with caspase-1 and NLRP3 was detected as shown by proximity ligation assay. Markers of neuroinflammation including microgliosis and elevated brain IL-1β expression were also observed. Importantly, these findings were further exacerbated in Sirt3−/− mice when fed a calorie-rich western diet. The observations of this study suggest that SIRT3 deficiency-induced brain mitochondrial dysfunction and neuroinflammation in metabolic syndrome may play a role in late-life cognitive decline.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
影响因子：
64.8
作者：
Guarente, Leonard
通讯作者：
Guarente, Leonard
DOI：
10.1073/pnas.1006586107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu
影响因子：
29
作者：
Anderson KA;Huynh FK;Fisher-Wellman K;Stuart JD;Peterson BS;Douros JD;Wagner GR;Thompson JW;Madsen AS;Green MF;Sivley RM;Ilkayeva OR;Stevens RD;Backos DS;Capra JA;Olsen CA;Campbell JE;Muoio DM;Grimsrud PA;Hirschey MD
通讯作者：
Hirschey MD
SIRT3介导多组织耦合以进行代谢燃料开关。
影响因子：
29
作者：
Dittenhafer-Reed KE;Richards AL;Fan J;Smallegan MJ;Fotuhi Siahpirani A;Kemmerer ZA;Prolla TA;Roy S;Coon JJ;Denu JM
通讯作者：
Denu JM