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

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)677-688
Number of pages12
JournalMetabolism: Clinical and Experimental
Volume64
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

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Mitochondrial Dynamics
Mitochondrial Membranes
Type 2 Diabetes Mellitus
Transgenic Mice
White Adipose Tissue
HSP70 Heat-Shock Proteins
Mitochondrial Proteins
Sucrose
Insulin Resistance
Mitochondria
Obesity
Fats
Gene Expression
Gene Fusion
Streptozocin
Adipocytes
Membrane Potentials
Adenosine Triphosphatases
Hydrolysis
Adenosine Triphosphate

Keywords

  • Fission
  • Fusion
  • Preprotein import
  • Reactive oxygen species

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

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

In: Metabolism: Clinical and Experimental, Vol. 64, No. 6, 01.06.2015, p. 677-688.

Research output: Contribution to journalArticle

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. / Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes. In: Metabolism: Clinical and Experimental. 2015 ; Vol. 64, No. 6. pp. 677-688.
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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

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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