Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

Watanabe, Tomoyuki; Saotome, Masao; Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi; Funaki, Makoto; Hayashi, Hideharu

doi:10.1016/J.YEXCR.2014.02.027

Title: Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

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Abstract

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction,more »« less

Authors:

Watanabe, Tomoyuki ^[1]; Saotome, Masao ^[1]; Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi ^[1]; Funaki, Makoto ^[2]; Hayashi, Hideharu ^[1]

Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan)
Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1 Kuramoto-cho, Tokushima 770-8503 (Japan)

Publication Date:: Thu May 01 00:00:00 EDT 2014

OSTI Identifier:: 22395894

Resource Type:: Journal Article

Journal Name:: Experimental Cell Research

Additional Journal Information:: Journal Volume: 323; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; CARDIOVASCULAR DISEASES; GLUCOSE; HYDROGEN PEROXIDE; INSULIN; LIPIDS; METABOLITES; MITOCHONDRIA; OXYGEN; PATHOGENESIS; PORPHYRINS; UPTAKE

Citation Formats


                    Watanabe, Tomoyuki, Saotome, Masao, Nobuhara, Mamoru, Sakamoto, Atsushi, Urushida, Tsuyoshi, Katoh, Hideki, Satoh, Hiroshi, Funaki, Makoto, and Hayashi, Hideharu. Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance.  United States: N. p., 2014. 
        Web.  doi:10.1016/J.YEXCR.2014.02.027.

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                    Watanabe, Tomoyuki, Saotome, Masao, Nobuhara, Mamoru, Sakamoto, Atsushi, Urushida, Tsuyoshi, Katoh, Hideki, Satoh, Hiroshi, Funaki, Makoto, & Hayashi, Hideharu. Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance.  United States.  https://doi.org/10.1016/J.YEXCR.2014.02.027

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                    Watanabe, Tomoyuki, Saotome, Masao, Nobuhara, Mamoru, Sakamoto, Atsushi, Urushida, Tsuyoshi, Katoh, Hideki, Satoh, Hiroshi, Funaki, Makoto, and Hayashi, Hideharu. 2014.  
        "Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance".  United States.  https://doi.org/10.1016/J.YEXCR.2014.02.027.

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@article{osti_22395894,

  title        = {Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance},

  author       = {Watanabe, Tomoyuki and Saotome, Masao and Nobuhara, Mamoru and Sakamoto, Atsushi and Urushida, Tsuyoshi and Katoh, Hideki and Satoh, Hiroshi and Funaki, Makoto and Hayashi, Hideharu},

  abstractNote = {Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance. • Inhibition of DRP or ROS failed to improve palmitate-induced insulin-resistance. • Mitochondrial dysfunction by lipid metabolites would induce insulin-resistance.},

  doi          = {10.1016/J.YEXCR.2014.02.027},

  url          = {https://www.osti.gov/biblio/22395894},
  journal      = {Experimental Cell Research},

  issn         = {0014-4827},

  number       = 2,

  volume       = 323,

  place        = {United States},

  year         = {Thu May 01 00:00:00 EDT 2014},

  month        = {Thu May 01 00:00:00 EDT 2014}

}

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