title: Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨm) 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 (H2O2), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨm depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H2O2-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 ΔΨm 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.
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Electronic address: msaotome@hama-med.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Saotome
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Nobuhara
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Urushida
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Katoh
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.affiliation: Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Funaki
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D002460:Cell Line; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D007328:Insulin; D010168:Palmitates; D011166:Porphyrins; D017382:Reactive Oxygen Species; C021096:tetra(4-N-methylpyridyl)porphine; D006861:Hydrogen Peroxide; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: Dynamin-related protein-1; Mitochondrial fragmentation; Myocardial insulin resistance; Reactive oxygen species; Saturated fatty acid