Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Transl Med. 2023 Jul 22;21(1):494. doi: 10.1186/s12967-023-04246-9.
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 Ca 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.
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，很可能是由于线粒体相关膜（MAMs）的过度形成。Sirtuin3（SIRT3）是一种关键的线粒体 NAD 依赖性去乙酰化酶，对线粒体功能的动态平衡至关重要，并且与神经病理学密切相关。然而，SIRT3 调节 MAM 偶联的作用尚不清楚。
采用链脲佐菌素（STZ）诱导的糖尿病小鼠和高糖处理的 SH-SY5Y 细胞分别建立动物和细胞模型。在体内，通过腺相关病毒上调小鼠海马中的 SIRT3 表达，在体外，通过重组慢病毒载体上调 SIRT3 表达。使用行为测试评估认知功能。使用高尔基和尼氏染色评估海马损伤。使用 Western blot 和 TUNEL 检测分析细胞凋亡。使用流式细胞术和共聚焦荧光显微镜检测线粒体功能。使用 VDAC1-GRP75-IP3R 复合物的免疫共沉淀、内质网和线粒体共定位的荧光成像以及 MAMs 结构分析的透射电子显微镜来研究机制。
我们的结果表明，SIRT3 在高糖处理的 SH-SY5Y 细胞和糖尿病小鼠海马组织中的表达明显降低。此外，上调 SIRT3 可减轻糖尿病小鼠的海马损伤和认知障碍，并减轻线粒体 Ca2+超载诱导的线粒体功能障碍和细胞凋亡。机制上，在高糖条件下，MAM 的形成增强，而通过体外和体内遗传上调 SIRT3 减少 VDAC1-GRP75-IP3R 复合物的相互作用，这种形成被逆转。此外，我们通过 honokiol 治疗研究了 SIRT3 的药理学激活对糖尿病小鼠的治疗效果，结果显示与我们的遗传干预具有相似的效果。
总之，我们的研究结果表明，SIRT3 通过限制异常 MAM 的形成改善糖尿病小鼠的认知障碍。此外，通过 honokiol 靶向 SIRT3 的激活为糖尿病相关认知功能障碍提供了一种有前途的治疗候选物。总的来说，我们的研究表明 SIRT3 在调节 MAM 偶联方面具有新的作用，并表明 SIRT3 靶向治疗对糖尿病痴呆患者有希望。
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