Perturbed Brain Glucose Metabolism Caused by Absent SIRT3 Activity.
Perturbed Brain Glucose Metabolism Caused by Absent SIRT3 Activity.
复制标题
DOI：
10.3390/cells10092348
复制
发表时间：
2021-09-08
期刊：
影响因子：
6
通讯作者：
McKenna MC
中科院分区：
文献类型：
--
作者：
Kristian T;Karimi AJ;Fearnow A;Waddell J;McKenna MC
乙酰化是一种翻译后修饰，其调节基本上参与细胞和线粒体生物能量代谢的酶的活性。NAD+依赖性去乙酰化酶sirtuin 3（SIRT 3）定位于线粒体，在其中其在调节TCA循环酶和线粒体呼吸复合物的乙酰化中起关键作用。虽然已经鉴定了线粒体中的SIRT 3靶蛋白，但SIRT 3活性对脑中线粒体葡萄糖代谢的影响仍然难以捉摸。使用离体13 C-NMR光谱法在注射[1，6 - 13 C]葡萄糖的SIRT 3敲除（KO）和野生型（WT）小鼠中确定SIRT 3活性消除对葡萄糖代谢的影响。1H-NMR光谱和氨基酸分析显示SIRT 3 KO和WT小鼠之间的乳酸盐、谷氨酸盐、丙氨酸、琥珀酸盐或天冬氨酸盐浓度无差异。然而，谷氨酰胺、总肌酸（Cr）和GABA在SIRT 3 KO脑中较低。在SIRT 3 KO脑中，来自[1，6 - 13 C]葡萄糖代谢的标记掺入乳酸或丙氨酸不受影响。然而，在SIRT 3 KO脑中，标记物掺入谷氨酸、谷氨酰胺、GABA和天冬氨酸的所有同位素异构体中较低，反映了神经元和星形胶质细胞中线粒体和TCA循环代谢的活性降低。这很可能是由于SIRT 3 KO小鼠脑中SIRT 3活性受抑制导致线粒体酶的过度乙酰化。因此，Sirt 3的缺失导致脑中线粒体氧化能量代谢和神经递质合成受损。由于SIRT 3活性是NAD+依赖性的，因此这些结果可能与线粒体NAD+库中病理性减少下的葡萄糖代谢变化平行。
Acetylation is a post-translational modification that regulates the activity of enzymes fundamentally involved in cellular and mitochondrial bioenergetic metabolism. NAD+ dependent deacetylase sirtuin 3 (SIRT3) is localized to mitochondria where it plays a key role in regulating acetylation of TCA cycle enzymes and the mitochondrial respiratory complexes. Although the SIRT3 target proteins in mitochondria have been identified, the effect of SIRT3 activity on mitochondrial glucose metabolism in the brain remains elusive. The impact of abolished SIRT3 activity on glucose metabolism was determined in SIRT3 knockout (KO) and wild type (WT) mice injected with [1,6-13C]glucose using ex vivo 13C-NMR spectroscopy. The 1H-NMR spectra and amino acid analysis showed no differences in the concentration of lactate, glutamate, alanine, succinate, or aspartate between SIRT3 KO and WT mice. However, glutamine, total creatine (Cr), and GABA were lower in SIRT3 KO brain. Incorporation of label from [1,6-13C]glucose metabolism into lactate or alanine was not affected in SIRT3 KO brain. However, the incorporation of the label into all isotopomers of glutamate, glutamine, GABA and aspartate was lower in SIRT3 KO brain, reflecting decreased activity of mitochondrial and TCA cycle metabolism in both neurons and astrocytes. This is most likely due to hyperacetylation of mitochondrial enzymes due to suppressed SIRT3 activity in the brain of SIRT3 KO mice. Thus, the absence of Sirt3 results in impaired mitochondrial oxidative energy metabolism and neurotransmitter synthesis in the brain. Since the SIRT3 activity is NAD+ dependent, these results might parallel changes in glucose metabolism under pathologic reduction in mitochondrial NAD+ pools.
登录
查看更多内容
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：
6.4
作者：
Anderson KA;Hirschey MD
通讯作者：
Hirschey MD
影响因子：
8.8
作者：
Gonzalez Herrera KN;Zaganjor E;Ishikawa Y;Spinelli JB;Yoon H;Lin JR;Satterstrom FK;Ringel A;Mulei S;Souza A;Gorham JM;Benson CC;Seidman JG;Sorger PK;Clish CB;Haigis MC
通讯作者：
Haigis MC
影响因子：
11.2
作者：
Sawant Dessai A;Dominguez MP;Chen UI;Hasper J;Prechtl C;Yu C;Katsuta E;Dai T;Zhu B;Jung SY;Putluri N;Takabe K;Zhang XH;O'Malley BW;Dasgupta S
通讯作者：
Dasgupta S
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