title: VAMP7 Regulates Autophagy to Maintain Mitochondrial Homeostasis and to Control Insulin Secretion in Pancreatic β-Cells.
abstract: VAMP7 is a SNARE protein that mediates specific membrane fusions in intracellular trafficking and was recently reported to regulate autophagosome formation. However, its function in pancreatic β-cells is largely unknown. To elucidate the physiological role of VAMP7 in β-cells, we generated pancreatic β-cell-specific VAMP7 knockout (Vamp7(flox/Y);Cre) mice. VAMP7 deletion impaired glucose-stimulated ATP production and insulin secretion, though VAMP7 was not localized to insulin granules. VAMP7-deficient β-cells showed defective autophagosome formation and reduced mitochondrial function. p62/SQSTM1, a marker protein for defective autophagy, was selectively accumulated on mitochondria in VAMP7-deficient β-cells. These findings suggest that accumulation of dysfunctional mitochondria that are degraded by autophagy caused impairment of glucose-stimulated ATP production and insulin secretion in Vamp7(flox/Y);Cre β-cells. Feeding a high-fat diet to Vamp7(flox/Y);Cre mice exacerbated mitochondrial dysfunction, further decreased ATP production and insulin secretion, and consequently induced glucose intolerance. Moreover, we found upregulated VAMP7 expression in wild-type mice fed a high-fat diet and in db/db mice, a model for diabetes. Thus our data indicate that VAMP7 regulates autophagy to maintain mitochondrial quality and insulin secretion in response to pathological stress in β-cells.
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Aoyagi
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Mica
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.affiliation: Department of Biochemistry, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Itakura
authors.affiliation: Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Torii
authors.affiliation: Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Akimoto
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Chiyono
authors.initials: C
authors.lastname: Nishiwaki
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakamichi
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.affiliation: Department of Biochemistry, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan shinya@ks.kyorin-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D050683:R-SNARE Proteins / Q000172:deficiency / Q000502:physiology*
chemical_list: D007328:Insulin; D050683:R-SNARE Proteins; C496927:Sybl1 protein, mouse; D000255:Adenosine Triphosphate; D005947:Glucose