Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes.
Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes.
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DOI：
10.1016/j.metabol.2015.02.004
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Yu Wang;A. Katayama;Takahiro Terami;Xiaoying Han;Tomokazu Nunoue;Dong‐xia Zhang;S. Teshigawara;Jun Eguchi;A. Nakatsuka;K. Murakami;D. Ogawa;Y. Furuta;H. Makino;J. Wada
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文献类型：
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作者：
Yu Wang;A. Katayama;Takahiro Terami;Xiaoying Han;Tomokazu Nunoue;Dong‐xia Zhang;S. Teshigawara;Jun Eguchi;A. Nakatsuka;K. Murakami;D. Ogawa;Y. Furuta;H. Makino;J. Wada
目的在肥胖和2型糖尿病患者中，白色脂肪组织(WAT)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表达上调。在线粒体内膜上，Timm44将线粒体热休克蛋白70(MtHsp70)锚定在线粒体内膜23(TIM23)复合体的转位酶上，并依赖线粒体内膜电位和线粒体ATPase结构域上的ATP水解酶，促进线粒体靶向前蛋白进入线粒体基质。方法建立aP2启动子驱动的Timm44转基因(TG)小鼠模型，观察高脂高蔗糖(HFHS)喂养的TIMM44转基因小鼠对2型糖尿病和肥胖的保护作用。结果aP2启动子驱动的TIMM44转基因小鼠体重明显低于野生型小鼠。TIMM44Tg小鼠的胰岛素敏感性高于野生型小鼠。尽管喂食HFHS周的Timm44 TG小鼠的Wat重量没有改变，但脂肪细胞体积变小，并观察到线粒体融合与Dnm1和Fis1等裂变基因表达的减少有关。此外，与野生型相比，TIMM44转基因小鼠的OPA1、Mfn1、Mfn2和Mfn1融合基因的表达显著增加，并且TIMM44转基因小鼠也观察到线粒体融合。结论TIMM44基因可能是治疗2型糖尿病的新靶点。
ObjectiveIn 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.MethodsWe 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.ResultsThe 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 andFis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opa1,Mfn1andMfn2, andMfn1were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow.ConclusionsTheTimm44gene may be a new target for the treatment of type 2 diabetes.