Mitoribosome insufficiency in β cells is associated with type 2 diabetes-like islet failure

다국어 초록 (Multilingual Abstract)

Genetic variations in mitoribosomal subunits and mitochondrial transcription factors are related to type 2 diabetes. However, the role of islet mitoribosomes in the development of type 2 diabetes has not been determined. We investigated the effects of the mitoribosomal gene on β-cell function and glucose homeostasis. Mitoribosomal gene expression was analyzed in datasets from the NCBI GEO website (GSE25724, GSE76894, and GSE76895) and the European Nucleotide Archive (ERP017126), which contain the transcriptomes of type 2 diabetic and nondiabetic organ donors. We found deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1. The phenotypes of haploinsufficiency in a single mitoribosomal gene were examined using β-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1beta+/− mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased β-cell mass associated with higher expression of Reg family genes. However, Crif1beta+/− mice showed earlier islet failure in response to high-fat feeding, which was exacerbated by aging. Haploinsufficiency of a single mitoribosomal gene predisposes rodents to glucose intolerance, which resembles the early stages of type 2 diabetes in humans.

참고문헌 (Reference)

1 Zwiener, I., "Transforming RNA-Seq data to improve the performance of prognostic gene signatures" 9 : e85150-, 2014

2 Ji, Y., "Toll-like receptors TLR2 and TLR4 block the replication of pancreatic beta cells in diet-induced obesity" 20 : 677-686, 2019

3 Cerasi, E., "The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus" 55 : 278-304, 1967

4 Hatefi, Y., "The mitochondrial electron transport and oxidative phosphorylation system" 54 : 1015-1069, 1985

5 Del Prato, S., "The importance of first-phase insulin secretion : implications for the therapy of type 2 diabetes mellitus" 17 : 164-174, 2001

6 Rackham, O., "The human mitochondrial transcriptome and the RNA-binding proteins that regulate its expression" 3 : 675-695, 2012

7 Solimena, M., "Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes" 61 : 641-657, 2018

8 Greber, B. J., "Structure and function of the mitochondrial ribosome" 85 : 103-132, 2016

9 Segerstolpe, A., "Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes" 24 : 593-607, 2016

10 Greber, B. J., "Ribosome. The complete structure of the 55S mammalian mitochondrial ribosome" 348 : 303-308, 2015

11 Pearce, S. F., "Regulation of mammalian mitochondrial gene expression:recent advances" 42 : 625-639, 2017

12 Rorsman, P., "Regulation of calcium in pancreatic alpha-and beta-cells in health and disease" 51 : 300-308, 2012

13 Parikh, A., "Regenerating proteins and their expression, regulation and signaling" 3 : 57-70, 2012

14 Li, Q., "Reg2 expression is required for pancreatic islet compensation in response to aging and high-fat diet-induced obesity" 158 : 1634-1644, 2017

15 Planas, R., "Reg(regenerating)gene overexpression in islets from non-obese diabetic mice with accelerated diabetes : role of IFNbeta" 49 : 2379-2387, 2006

16 Thurmond, D. C., "Recent insights into beta-cell exocytosis in Type 2 diabetes" 432 : 1310-1325, 2020

17 Marselli, L., "Persistent or transient human beta cell dysfunction induced by metabolic stress : specific signatures and shared gene expression with Type 2diabetes" 33 : 108466-, 2020

18 Sone, H., "Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice" 48 : 58-67, 2005

19 Ott, M., "Organization and regulation of mitochondrial protein synthesis" 85 : 77-101, 2016

20 Kharouta, M., "No mantle formation in rodent islets—the prototype of islet revisited" 85 : 252-257, 2009

21 Kim, H. J., "Mitochondrial ribosomes in cancer" 47 : 67-81, 2017

22 De Silva, D., "Mitochondrial ribosome assembly in health and disease" 14 : 2226-2250, 2015

23 Sylvester, J. E., "Mitochondrial ribosomal proteins : candidate genes for mitochondrial disease" 6 : 73-80, 2004

24 Ritz, P., "Mitochondrial function, energy expenditure, aging and insulin resistance" 31 (31): 5S67-65S73, 2005

25 Maechler, P., "Mitochondrial function in normal and diabetic beta-cells" 414 : 807-812, 2001

26 Liesa, M., "Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure" 17 : 491-506, 2013

27 Davies, M. J., "Loss of the first phase insulin response to intravenous glucose in subjects with persistent impaired glucose tolerance" 11 : 432-436, 1994

28 Supale, S., "Loss of prohibitin induces mitochondrial damages altering betacell function and survival and is responsible for gradual diabetes development" 62 : 3488-3499, 2013

29 Sharoyko, V. V., "Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes" 23 : 5733-5749, 2014

30 Wojtusciszyn, A., "Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts" 51 : 1843-1852, 2008

31 Ahren, J., "Increased beta-cell volume in mice fed a high-fat diet : a dynamic study over 12 months" 2 : 353-356, 2010

32 Brouwers, B., "Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression" 20 : 979-990, 2014

33 Schulla, V., "Impaired insulin secretion and glucose tolerance in beta cellselective Ca(v)1.2 Ca2+ channel null mice" 22 : 3844-3854, 2003

34 Silva, J. P., "Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes" 26 : 336-340, 2000

35 Ostenson, C. G., "Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients" 55 : 435-440, 2006

36 Daniel, S., "Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion" 48 : 1686-1690, 1999

37 Pipeleers, D., "Glucose-induced insulin release depends on functional cooperation between islet cells" 79 : 7322-7325, 1982

38 Gandasi, N. R., "Glucose-dependent granule docking limits insulin secretion and is decreased in human Type 2 diabetes" 27 : 470-478.e474, 2018

39 Chen, Z., "Four decades after the discovery of Regenerating Islet-Derived (Reg) proteins: current understanding and challenges" 7 : 235-, 2019

40 Seino, S., "Dynamics of insulin secretion and the clinical implications for obesity and diabetes" 121 : 2118-2125, 2011

41 Kim, Y. K., "Disruption of CR6-interacting factor-1(CRIF1)in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure" 58 : 771-780, 2015

42 Hull, R. L., "Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation" 48 : 1350-1358, 2005

43 Kim, K., "Degradation of PHLPP2 by KCTD17, via a glucagon-dependent pathway, promotes hepatic steatosis" 153 : 1568-1580.e1510, 2017

44 Nagamatsu, S., "Decreased expression of t-SNARE, syntaxin 1, and SNAP-25 in pancreatic beta-cells is involved in impaired insulin secretion from diabetic GK rat islets: restoration of decreased t-SNARE proteins improves impaired insulin secretion" 48 : 2367-2373, 1999

45 Kwon, M. C., "Crif1 is a novel transcriptional coactivator of STAT3" 27 : 642-653, 2008

46 Dominguez, V., "Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells" 286 : 4216-4225, 2011

47 Tseng, Y. H., "Cellular bioenergetics as a target for obesity therapy" 9 : 465-482, 2010

48 Pedersen, M. G., "Calcium signaling and secretory granule pool dynamics underlie biphasic insulin secretion and its amplification by glucose : experiments and modeling" 316 : E475-E486, 2019

49 Kim, S. J., "CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane" 16 : 274-283, 2012

50 Ghanemi, A., "Broken energy homeostasis and obesity pathogenesis : the surrounding concepts" 7 : 453-, 2018

51 Ebrahimi, A. G., "Beta cell identity changes with mild hyperglycemia: implications for function, growth, and vulnerability" 35 : 100959-, 2020

52 Cheadle, C., "Analysis of microarray data using Z score transformation" 5 : 73-81, 2003

53 Kilimnik, G., "Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes" 6 : e27445-, 2011

54 Li, D. S., "A protocol for islet isolation from mouse pancreas" 4 : 1649-1652, 2009

55 Wikstrom, J. D., "A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets" 7 : e33023-, 2012