线粒体内膜转位酶44改变线粒体融合与分裂动力学并预防2型糖尿病。

Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes.

作者信息

Wang Yu, Katayama Akihiro, Terami Takahiro, Han Xiaoying, Nunoue Tomokazu, Zhang Dongxiao, Teshigawara Sanae, Eguchi Jun, Nakatsuka Atsuko, Murakami Kazutoshi, Ogawa Daisuke, Furuta Yasuhide, Makino Hirofumi, Wada Jun

机构信息

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan; Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Canada, H3T 1E2.

出版信息

Metabolism. 2015 Jun;64(6):677-88. doi: 10.1016/j.metabol.2015.02.004. Epub 2015 Feb 23.

DOI:10.1016/j.metabol.2015.02.004

PMID:25749183

Abstract

OBJECTIVE

In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70.

METHODS

We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity.

RESULTS

The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm1l and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opa1, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow.

CONCLUSIONS

The Timm44 gene may be a new target for the treatment of type 2 diabetes.

摘要

目的

在肥胖和2型糖尿病中，白色脂肪组织（WAT）中线粒体功能受损与全身胰岛素敏感性降低有关。Timm44在链脲佐菌素诱导的糖尿病小鼠肾脏中上调。在内线粒体膜中，Timm44将线粒体热休克蛋白70（mtHsp70）锚定到内膜转位酶23（TIM23）复合物上，并促进依赖内膜电位和mtHsp70的ATP酶结构域上的ATP水解，将靶向线粒体的前体蛋白导入线粒体基质。

方法

我们构建了aP2启动子驱动的Timm44转基因（Tg）小鼠模型，并研究喂食高脂/高糖（HFHS）饲料的Timm44 Tg小鼠是否能预防2型糖尿病和肥胖。

结果

aP2启动子驱动的Timm44 Tg小鼠的体重低于野生型小鼠，且Timm44 Tg小鼠的胰岛素敏感性高于野生型小鼠。尽管喂食HFHS饲料的Timm44 Tg小鼠的WAT重量未改变，但脂肪细胞大小减小，并且观察到与裂变基因（如Dnm1l和Fis1）表达降低相关的线粒体融合。此外，当喂食标准（STD）饲料时，与野生型小鼠相比，Timm44 Tg小鼠中融合基因Opa1、Mfn1和Mfn2以及Mfn1的表达显著增加，并且在喂食STD饲料的Timm44 Tg小鼠中也观察到融合的线粒体。