Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells
Objective: Insulin release from pancreatic β-cells is controlled by plasma glucose levels via mitochondrial fuel metabolism. Therefore, insulin secretion is critically dependent on mitochondrial DNA (mtDNA) and the genes it encodes. Mitochondrial transcription factor B2 (TFB2M) controls transcriptio...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-07-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817302430 |
| _version_ | 1819261850448035840 |
|---|---|
| author | Lisa M. Nicholas Bérengère Valtat Anya Medina Lotta Andersson Mia Abels Inês G. Mollet Deepak Jain Lena Eliasson Nils Wierup Malin Fex Hindrik Mulder |
| author_facet | Lisa M. Nicholas Bérengère Valtat Anya Medina Lotta Andersson Mia Abels Inês G. Mollet Deepak Jain Lena Eliasson Nils Wierup Malin Fex Hindrik Mulder |
| author_sort | Lisa M. Nicholas |
| collection | DOAJ |
| description | Objective: Insulin release from pancreatic β-cells is controlled by plasma glucose levels via mitochondrial fuel metabolism. Therefore, insulin secretion is critically dependent on mitochondrial DNA (mtDNA) and the genes it encodes. Mitochondrial transcription factor B2 (TFB2M) controls transcription of mitochondrial-encoded genes. However, its precise role in mitochondrial metabolism in pancreatic β-cells and, consequently, in insulin secretion remains unknown.
Methods: To elucidate the role of TFB2M in mitochondrial function and insulin secretion in vitro and in vivo, mice with a β-cell specific homozygous or heterozygous knockout of Tfb2m and rat clonal insulin-producing cells in which the gene was silenced were examined with an array of metabolic and functional assays.
Results: There was an effect of gene dosage on Tfb2m expression and function. Loss of Tfb2m led to diabetes due to disrupted transcription of mitochondrial DNA (mtDNA) and reduced mtDNA content. The ensuing mitochondrial dysfunction activated compensatory mechanisms aiming to limit cellular dysfunction and damage of β-cells. These processes included the mitochondrial unfolded protein response, mitophagy, and autophagy. Ultimately, however, these cell-protective systems were overridden, leading to mitochondrial dysfunction and activation of mitochondrial-dependent apoptotic pathways. In this way, β-cell function and mass were reduced. Together, these perturbations resulted in impaired insulin secretion, progressive hyperglycemia, and, ultimately, development of diabetes.
Conclusions: Loss of Tfb2m in pancreatic β-cells results in progressive mitochondrial dysfunction. Consequently, insulin secretion in response to metabolic stimuli is impaired and β-cell mass reduced. Our findings indicate that TFB2M plays an important functional role in pancreatic β-cells. Perturbations of its actions may lead to loss of functional β-cell mass, a hallmark of T2D. |
| first_indexed | 2024-12-23T19:48:21Z |
| format | Article |
| id | doaj.art-7c8420984bd24f1c94b700a9d5958e76 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-23T19:48:21Z |
| publishDate | 2017-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-7c8420984bd24f1c94b700a9d5958e762022-12-21T17:33:28ZengElsevierMolecular Metabolism2212-87782017-07-016765166310.1016/j.molmet.2017.05.005Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cellsLisa M. Nicholas0Bérengère Valtat1Anya Medina2Lotta Andersson3Mia Abels4Inês G. Mollet5Deepak Jain6Lena Eliasson7Nils Wierup8Malin Fex9Hindrik Mulder10Department of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDeparment of Experimental Medical Science, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenDepartment of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Skåne University Hospital, 20502, Malmö, SwedenObjective: Insulin release from pancreatic β-cells is controlled by plasma glucose levels via mitochondrial fuel metabolism. Therefore, insulin secretion is critically dependent on mitochondrial DNA (mtDNA) and the genes it encodes. Mitochondrial transcription factor B2 (TFB2M) controls transcription of mitochondrial-encoded genes. However, its precise role in mitochondrial metabolism in pancreatic β-cells and, consequently, in insulin secretion remains unknown. Methods: To elucidate the role of TFB2M in mitochondrial function and insulin secretion in vitro and in vivo, mice with a β-cell specific homozygous or heterozygous knockout of Tfb2m and rat clonal insulin-producing cells in which the gene was silenced were examined with an array of metabolic and functional assays. Results: There was an effect of gene dosage on Tfb2m expression and function. Loss of Tfb2m led to diabetes due to disrupted transcription of mitochondrial DNA (mtDNA) and reduced mtDNA content. The ensuing mitochondrial dysfunction activated compensatory mechanisms aiming to limit cellular dysfunction and damage of β-cells. These processes included the mitochondrial unfolded protein response, mitophagy, and autophagy. Ultimately, however, these cell-protective systems were overridden, leading to mitochondrial dysfunction and activation of mitochondrial-dependent apoptotic pathways. In this way, β-cell function and mass were reduced. Together, these perturbations resulted in impaired insulin secretion, progressive hyperglycemia, and, ultimately, development of diabetes. Conclusions: Loss of Tfb2m in pancreatic β-cells results in progressive mitochondrial dysfunction. Consequently, insulin secretion in response to metabolic stimuli is impaired and β-cell mass reduced. Our findings indicate that TFB2M plays an important functional role in pancreatic β-cells. Perturbations of its actions may lead to loss of functional β-cell mass, a hallmark of T2D.http://www.sciencedirect.com/science/article/pii/S2212877817302430Mitochondrial metabolismPancreatic β-cellsInsulin secretion |
| spellingShingle | Lisa M. Nicholas Bérengère Valtat Anya Medina Lotta Andersson Mia Abels Inês G. Mollet Deepak Jain Lena Eliasson Nils Wierup Malin Fex Hindrik Mulder Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells Molecular Metabolism Mitochondrial metabolism Pancreatic β-cells Insulin secretion |
| title | Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells |
| title_full | Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells |
| title_fullStr | Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells |
| title_full_unstemmed | Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells |
| title_short | Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells |
| title_sort | mitochondrial transcription factor b2 is essential for mitochondrial and cellular function in pancreatic β cells |
| topic | Mitochondrial metabolism Pancreatic β-cells Insulin secretion |
| url | http://www.sciencedirect.com/science/article/pii/S2212877817302430 |
| work_keys_str_mv | AT lisamnicholas mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT berengerevaltat mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT anyamedina mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT lottaandersson mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT miaabels mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT inesgmollet mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT deepakjain mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT lenaeliasson mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT nilswierup mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT malinfex mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells AT hindrikmulder mitochondrialtranscriptionfactorb2isessentialformitochondrialandcellularfunctioninpancreaticbcells |