title: Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.
abstract: We have previously identified transcription factor B1 mitochondrial (TFB1M) as a type 2 diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D, we created a β-cell-specific knockout of Tfb1m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1m(-/-) mice exhibited retarded glucose clearance owing to impaired insulin secretion. β-Tfb1m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine dimethylation of 12S ribosomal RNA (rRNA). Here, we found that the levels of TFB1M and mitochondrial-encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1m(-/-) islets. Furthermore, the levels of reactive oxygen species (ROS) in response to cellular stress were increased whereas induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4(+) cells in the islets. Taken together, our findings demonstrate that Tfb1m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes owing to combined loss of β-cell function and mass. These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D.
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Sharoyko
authors.affiliation: Unit of Neuroendocrine Cell Biology.
authors.forename: Mia
authors.initials: M
authors.lastname: Abels
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Jiangming
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nicholas
authors.affiliation: Unit of Islet Cell Exocytosis and.
authors.forename: Ines Guerra
authors.initials: IG
authors.lastname: Mollet
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Jelena A
authors.initials: JA
authors.lastname: Stamenkovic
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Isabel
authors.initials: I
authors.lastname: Göhring
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Siri
authors.initials: S
authors.lastname: Malmgren
authors.affiliation: Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Clinical Research Centre, Skåne University Hospital, 205 02 Malmö, Sweden and.
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.affiliation: Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Clinical Research Centre, Skåne University Hospital, 205 02 Malmö, Sweden and.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism.
authors.forename: Peter
authors.initials: P
authors.lastname: Spégel
authors.affiliation: Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
authors.forename: Metodi D
authors.initials: MD
authors.lastname: Metodiev
authors.affiliation: Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.affiliation: Unit of Islet Cell Exocytosis and.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Unit of Neuroendocrine Cell Biology.
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.affiliation: Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, hindrik.mulder@med.lu.se.
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C462441:Tfb1m protein, mouse; D014157:Transcription Factors