PMID- 34019639 OWN - NLM STAT- MEDLINE DCOM- 20211007 LR - 20231111 IS - 1945-7170 (Electronic) IS - 0013-7227 (Print) IS - 0013-7227 (Linking) VI - 162 IP - 7 DP - 2021 Jul 1 TI - Tafazzin Deficiency Reduces Basal Insulin Secretion and Mitochondrial Function in Pancreatic Islets From Male Mice. LID - 10.1210/endocr/bqab102 [doi] LID - bqab102 AB - Tafazzin (TAZ) is a cardiolipin (CL) biosynthetic enzyme important for maintaining mitochondrial function. TAZ affects both the species and content of CL in the inner mitochondrial membrane, which are essential for normal cellular respiration. In pancreatic beta cells, mitochondrial function is closely associated with insulin secretion. However, the role of TAZ and CL in the secretion of insulin from pancreatic islets remains unknown. Male 4-month-old doxycycline-inducible TAZ knock-down (KD) mice and wild-type littermate controls were used. Immunohistochemistry was used to assess beta-cell morphology in whole pancreas sections, whereas ex vivo insulin secretion, CL content, RNA-sequencing analysis, and mitochondrial oxygen consumption were measured from isolated islet preparations. Ex vivo insulin secretion under nonstimulatory low-glucose concentrations was reduced ~52% from islets isolated from TAZ KD mice. Mitochondrial oxygen consumption under low-glucose conditions was also reduced ~58% in islets from TAZ KD animals. TAZ deficiency in pancreatic islets was associated with significant alteration in CL molecular species and elevated polyunsaturated fatty acid CL content. In addition, RNA-sequencing of isolated islets showed that TAZ KD increased expression of extracellular matrix genes, which are linked to pancreatic fibrosis, activated stellate cells, and impaired beta-cell function. These data indicate a novel role for TAZ in regulating pancreatic islet function, particularly under low-glucose conditions. CI - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Cole, Laura K AU - Cole LK AD - Department of Pharmacology, Winnipeg, R3E3P4, Canada. AD - Department of Therapeutics, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Agarwal, Prasoon AU - Agarwal P AD - KTH Royal Institute of Technology, School of Electrical Engineering and Computer Science, 10044 Stockholm, Sweden. AD - Science for Life Laboratory, 16939 Solna, Sweden. FAU - Doucette, Christine A AU - Doucette CA AD - Physiology and Pathophysiology, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Fonseca, Mario AU - Fonseca M AD - Department of Pharmacology, Winnipeg, R3E3P4, Canada. AD - Department of Therapeutics, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Xiang, Bo AU - Xiang B AD - Department of Pharmacology, Winnipeg, R3E3P4, Canada. AD - Department of Therapeutics, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Sparagna, Genevieve C AU - Sparagna GC AD - Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA. FAU - Seshadri, Nivedita AU - Seshadri N AD - Physiology and Pathophysiology, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Vandel, Marilyne AU - Vandel M AD - Department of Pharmacology, Winnipeg, R3E3P4, Canada. AD - Department of Therapeutics, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Dolinsky, Vernon W AU - Dolinsky VW AD - Department of Pharmacology, Winnipeg, R3E3P4, Canada. AD - Department of Therapeutics, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. FAU - Hatch, Grant M AU - Hatch GM AUID- ORCID: 0000-0002-1568-6071 AD - Department of Pharmacology, Winnipeg, R3E3P4, Canada. AD - Department of Therapeutics, Winnipeg, R3E3P4, Canada. AD - Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Faculty of Health Sciences, University of Manitoba, Winnipeg, R3E3P4, Canada. LA - eng GR - 144626/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Endocrinology JT - Endocrinology JID - 0375040 RN - 0 (Cardiolipins) RN - 0 (Fatty Acids, Unsaturated) RN - EC 2.3.- (Acyltransferases) RN - EC 2.3.- (tafazzin protein, mouse) RN - N12000U13O (Doxycycline) SB - IM MH - Acyltransferases/*deficiency/genetics/*physiology MH - Animals MH - Cardiolipins/analysis/chemistry MH - Doxycycline/pharmacology MH - Fatty Acids, Unsaturated/analysis MH - Female MH - Fibrosis MH - Gene Knockdown Techniques MH - Insulin Secretion/*physiology MH - Islets of Langerhans/chemistry/*physiology/ultrastructure MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Mitochondria/*physiology MH - Oxidation-Reduction MH - Oxygen Consumption/physiology MH - Pancreas/pathology PMC - PMC8197286 OTO - NOTNLM OT - cardiolipin OT - insulin secretion OT - mitochondrial respiration OT - pancreatic islet function OT - tafazzin EDAT- 2021/05/22 06:00 MHDA- 2021/10/08 06:00 PMCR- 2022/05/21 CRDT- 2021/05/21 17:21 PHST- 2021/03/10 00:00 [received] PHST- 2021/05/22 06:00 [pubmed] PHST- 2021/10/08 06:00 [medline] PHST- 2021/05/21 17:21 [entrez] PHST- 2022/05/21 00:00 [pmc-release] AID - 6279901 [pii] AID - bqab102 [pii] AID - 10.1210/endocr/bqab102 [doi] PST - ppublish SO - Endocrinology. 2021 Jul 1;162(7):bqab102. doi: 10.1210/endocr/bqab102.