SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes.
SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes.
复制标题
SIRT3通过调节与糖尿病相关的ER膜改善糖尿病相关的认知功能障碍
DOI：
10.1186/s12967-023-04246-9
复制
发表时间：
2023-07-22
影响因子：
7.4
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Chang, Yanmin;Wang, Cailin;Zhu, Jiahui;Zheng, Siyi;Sun, Shangqi;Wu, Yanqing;Jiang, Xingjun;Li, Lulu;Ma, Rong;Li, Gang
关键词：
糖尿病与认知能力下降和痴呆的风险增加有关。这些疾病与线粒体功能障碍有关，很可能是线粒体相关膜（MAMs）过度形成的结果。Sirtuin3 （SIRT3）是一种关键的线粒体NAD+依赖的去乙酰化酶，对线粒体功能稳态至关重要，并与神经病理高度相关。然而，SIRT3在调控MAM偶联中的作用尚不清楚。分别建立链脲佐菌素注射糖尿病小鼠和高糖处理SH-SY5Y细胞作为动物模型和细胞模型。体内用腺相关病毒在小鼠海马中上调SIRT3表达，体外用重组慢病毒载体上调SIRT3表达。使用行为测试评估认知功能。采用高尔基和尼氏染色评估海马损伤。western blotting和TUNEL法分析细胞凋亡。采用流式细胞术和共聚焦荧光显微镜检测线粒体功能。通过VDAC1-GRP75-IP3R复合物的共免疫沉淀、ER和线粒体共定位的荧光成像以及MAMs的透射电镜结构分析来研究其机制。我们的研究结果表明，在高糖处理的糖尿病小鼠SH-SY5Y细胞和海马组织中，SIRT3的表达显著降低。此外，上调SIRT3可减轻糖尿病小鼠海马损伤和认知障碍，减轻线粒体Ca2+超载引起的线粒体功能障碍和凋亡。在机制上，高糖条件下MAM的形成增强，而在体外和体内，通过减少VDAC1-GRP75-IP3R复合物的相互作用，SIRT3的基因上调可以逆转MAM的形成。此外，我们通过厚朴酚治疗研究了SIRT3的药理激活对糖尿病小鼠的治疗作用，其效果与我们的遗传干预相似。总之，我们的研究结果表明SIRT3通过限制异常的MAM形成来改善糖尿病小鼠的认知障碍。此外，以激活SIRT3为靶点的厚朴酚为糖尿病相关认知功能障碍的治疗提供了一个有希望的候选治疗方案。总之，我们的研究表明SIRT3在调节MAM偶联中的新作用，并表明SIRT3靶向治疗糖尿病痴呆患者是有希望的。在线版本包含补充材料，可在10.1186/s12967-023-04246-9获得。
Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown. Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1–GRP75–IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs. Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1–GRP75–IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions. In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients. The online version contains supplementary material available at 10.1186/s12967-023-04246-9.
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影响因子：
12.4
作者：
Guan C;Huang X;Yue J;Xiang H;Shaheen S;Jiang Z;Tao Y;Tu J;Liu Z;Yao Y;Yang W;Hou Z;Liu J;Yang XD;Zou Q;Su B;Liu Z;Ni J;Cheng J;Wu X
通讯作者：
Wu X
影响因子：
13.3
作者：
Gelmetti, Vania;De Rosa, Priscilla;Valente, Enza Maria
通讯作者：
Valente, Enza Maria
影响因子：
7
作者：
Zhao, Shanjiang;Gong, Jianfei;Wang, Yi;Heng, Nuo;Wang, Huan;Hu, Zhihui;Wang, Haoyu;Zhang, Haobo;Zhu, Huabin
通讯作者：
Zhu, Huabin
DOI：
10.18632/aging.101592
发表时间：
2018-10-23
期刊：
Aging
影响因子：
--
作者：
Yin J;Li S;Nielsen M;Carcione T;Liang WS;Shi J
通讯作者：
Shi J
影响因子：
5.6
作者：
Li, Ping;Newhardt, Maria F.;Matsuzaki, Satoshi;Eyster, Craig;Pranay, Atul;Peelor, Frederick F. I. I. I. I. I. I.;Batushansky, Albert;Kinter, Caroline;Subramani, Kumar;Subrahmanian, Sandeep;Ahamed, Jasimuddin;Yu, Pengchun;Kinter, Michael;Miller, Benjamin F.;Humphries, Kenneth M.
通讯作者：
Humphries, Kenneth M.