title: MitoNEET-Parkin Effects in Pancreatic α- and β-Cells, Cellular Survival, and Intrainsular Cross Talk.
abstract: Mitochondrial metabolism plays an integral role in glucose-stimulated insulin secretion (GSIS) in β-cells. In addition, the diabetogenic role of glucagon released from α-cells plays a major role in the etiology of both type 1 and type 2 diabetes because unopposed hyperglucagonemia is a pertinent contributor to diabetic hyperglycemia. Titrating expression levels of the mitochondrial protein mitoNEET is a powerful approach to fine-tune mitochondrial capacity of cells. Mechanistically, β-cell-specific mitoNEET induction causes hyperglycemia and glucose intolerance due to activation of a Parkin-dependent mitophagic pathway, leading to the formation of vacuoles and uniquely structured mitophagosomes. Induction of mitoNEET in α-cells leads to fasting-induced hypoglycemia and hypersecretion of insulin during GSIS. MitoNEET-challenged α-cells exert potent antiapoptotic effects on β-cells and prevent cellular dysfunction associated with mitoNEET overexpression in β-cells. These observations identify that reduced mitochondrial function in α-cells exerts potently protective effects on β-cells, preserving β-cell viability and mass.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Shiuhwei
authors.initials: S
authors.lastname: Chen
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Risheng
authors.initials: R
authors.lastname: Ye
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Qiong A
authors.initials: QA
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Spurgin
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Sanders
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Wen-Hong
authors.initials: WH
authors.lastname: Li
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Unger
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX philipp.scherer@utsouthwestern.edu.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005934:Glucagon / Q000096:biosynthesis; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020239:Receptor Cross-Talk; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D007328:Insulin; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; C519501:mitoNEET protein, mouse; D005934:Glucagon; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005947:Glucose