title: Diabetes Susceptibility Genes Pdx1 and Clec16a Function in a Pathway Regulating Mitophagy in β-Cells.
abstract: Mitophagy is a critical regulator of mitochondrial quality control and is necessary for elimination of dysfunctional mitochondria to maintain cellular respiration. Here, we report that the homeodomain transcription factor Pdx1, a gene associated with both type 2 diabetes and monogenic diabetes of the young, regulates mitophagy in pancreatic β-cells. Loss of Pdx1 leads to abnormal mitochondrial morphology and function as well as impaired mitochondrial turnover. High-throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates the expression of Clec16a, a type 1 diabetes gene and itself a key mediator of mitophagy through regulation of the E3 ubiquitin ligase Nrdp1. Indeed, expression of Clec16a and Nrdp1 are both reduced in Pdx1 haploinsufficient islets, and reduction of Pdx1 impairs fusion of autophagosomes containing mitochondria to lysosomes during mitophagy. Importantly, restoration of Clec16a expression after Pdx1 loss of function restores mitochondrial trafficking during mitophagy and improves mitochondrial respiration and glucose-stimulated insulin release. Thus, Pdx1 orchestrates nuclear control of mitochondrial function in part by controlling mitophagy through Clec16a. The novel Pdx1-Clec16a-Nrdp1 pathway we describe provides a genetic basis for the pathogenesis of mitochondrial dysfunction in multiple forms of diabetes that could be targeted for future therapies to improve β-cell function.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI ssol@med.umich.edu stoffers@mail.med.upenn.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Soleimanpour
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Alana M
authors.initials: AM
authors.lastname: Ferrari
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Raum
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: David N
authors.initials: DN
authors.lastname: Groff
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Juxiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Kaufman
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ssol@med.umich.edu stoffers@mail.med.upenn.edu.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D063306:Mitophagy / Q000502:physiology*; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D040081:Protein Array Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: C000591253:CLEC16A protein, mouse; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D012313:RNA; D004247:DNA; C435904:Rnf41 protein, mouse; D044767:Ubiquitin-Protein Ligases