TY - JOUR
T1 - Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes
AU - Wang, Yu
AU - Katayama, Akihiro
AU - Terami, Takahiro
AU - Han, Xiaoying
AU - Nunoue, Tomokazu
AU - Zhang, Dongxiao
AU - Teshigawara, Sanae
AU - Eguchi, Jun
AU - Nakatsuka, Atsuko
AU - Murakami, Kazutoshi
AU - Ogawa, Daisuke
AU - Furuta, Yasuhide
AU - Makino, Hirofumi
AU - Wada, Jun
N1 - Funding Information:
This work was supported by the JSPS Grant-in-Aid for Scientific Research , Grant Numbers ( 25126716 , 25461354 , 26293218 , 26461361 , and 26461362 ).
Funding Information:
WY, AK, TT, HX, TN, ST, JE, AN, and KM have nothing to declare. DO belongs to the Department of Diabetic Nephropathy endowed by Boehringer Ingelheim and receives grant support from Eli Lilly. HM is a consultant for AbbVie, Astellas, and Teijin, receives speaker honoraria from Astellas, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda, and Tanabe Mitsubishi, and receives grant support from Astellas, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, Mochida, MSD, Novartis, Novo Nordisk, Pfizer, Takeda, and Tanabe Mitsubishi. JW is a consultant for Astellas and Boehringer Ingelheim and receives speaker honoraria from Novartis, Boehringer Ingelheim, and Novo Nordisk.
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Fission
KW - Fusion
KW - Preprotein import
KW - Reactive oxygen species
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U2 - 10.1016/j.metabol.2015.02.004
DO - 10.1016/j.metabol.2015.02.004
M3 - Article
C2 - 25749183
AN - SCOPUS:84927965410
VL - 64
SP - 677
EP - 688
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
SN - 0026-0495
IS - 6
ER -
