Mitoribosome Insufficiency in β Cells is Associated with Type 2 Diabetes-like Islet Failure

Overview

Journal Exp Mol Med

Specialties Biochemistry
Molecular Biology

Date 2022 Jul 8

PMID 35804190

Authors

Hyun Jung Hong

Kyong Hye Joung

Yong Kyung Kim

Min Jeong Choi

Seul Gi Kang

Jung Tae Kim

Yea Eun Kang

Joon Young Chang

Joon Ho Moon

Sangmi Jun

Hyun-Joo Ro

Yujeong Lee

Hyeongseok Kim

Jae-Hyung Park

Baeki E Kang

Yunju Jo

Heejung Choi

Dongryeol Ryu

Chul-Ho Lee

Hail Kim

Kyu-Sang Park

Hyun Jin Kim

Minho Shong

Affiliations

Soon will be listed here.

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. Crif1 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, Crif1 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.

Citing Articles

Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome.

Zgadzay Y, Mirabello C, Wanes G, Panek T, Chauhan P, Nystedt B bioRxiv. 2025; .

PMID: 39896671 PMC: 11785013. DOI: 10.1101/2024.12.18.629302.

Co-regulation and synteny of GFM2 and NSA2 links ribosomal function in mitochondria and the cytosol with chronic kidney disease.

Zhang M, Hogstrand C, Pontrelli P, Malik A Mol Med. 2024; 30(1):176.

PMID: 39396937 PMC: 11476648. DOI: 10.1186/s10020-024-00930-8.

Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk.

Singh V, Itoh Y, DelOlio S, Hassan A, Naschberger A, Flygaard R Nat Commun. 2024; 15(1):4272.

PMID: 38769321 PMC: 11106087. DOI: 10.1038/s41467-024-48163-x.

Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes.

Rivera Nieves A, Wauford B, Fu A Front Mol Biosci. 2024; 11:1354199.

PMID: 38404962 PMC: 10884328. DOI: 10.3389/fmolb.2024.1354199.

Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging.

Min S, Kang G, Park J, Kim M Yonsei Med J. 2024; 65(2):55-69.

PMID: 38288646 PMC: 10827639. DOI: 10.3349/ymj.2023.0131.

References

Maechler P, Wollheim C . Mitochondrial function in normal and diabetic beta-cells. Nature. 2001; 414(6865):807-12. DOI: 10.1038/414807a. View

HATEFI Y . The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem. 1985; 54:1015-69. DOI: 10.1146/annurev.bi.54.070185.005055. View

Rackham O, Mercer T, Filipovska A . The human mitochondrial transcriptome and the RNA-binding proteins that regulate its expression. Wiley Interdiscip Rev RNA. 2012; 3(5):675-95. DOI: 10.1002/wrna.1128. View

Pearce S, Rebelo-Guiomar P, DSouza A, Powell C, Van Haute L, Minczuk M . Regulation of Mammalian Mitochondrial Gene Expression: Recent Advances. Trends Biochem Sci. 2017; 42(8):625-639. PMC: 5538620. DOI: 10.1016/j.tibs.2017.02.003. View

Ott M, Amunts A, Brown A . Organization and Regulation of Mitochondrial Protein Synthesis. Annu Rev Biochem. 2016; 85:77-101. DOI: 10.1146/annurev-biochem-060815-014334. View

Greber B, Ban N . Structure and Function of the Mitochondrial Ribosome. Annu Rev Biochem. 2016; 85:103-32. DOI: 10.1146/annurev-biochem-060815-014343. View

Sylvester J, Fischel-Ghodsian N, Mougey E, OBrien T . Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease. Genet Med. 2004; 6(2):73-80. DOI: 10.1097/01.gim.0000117333.21213.17. View

De Silva D, Tu Y, Amunts A, Fontanesi F, Barrientos A . Mitochondrial ribosome assembly in health and disease. Cell Cycle. 2015; 14(14):2226-50. PMC: 4615001. DOI: 10.1080/15384101.2015.1053672. View

Kim H, Maiti P, Barrientos A . Mitochondrial ribosomes in cancer. Semin Cancer Biol. 2017; 47:67-81. PMC: 5662495. DOI: 10.1016/j.semcancer.2017.04.004. View

10.

Greber B, Bieri P, Leibundgut M, Leitner A, Aebersold R, Boehringer D . Ribosome. The complete structure of the 55S mammalian mitochondrial ribosome. Science. 2015; 348(6232):303-8. DOI: 10.1126/science.aaa3872. View

11.

Kim S, Kwon M, Ryu M, Chung H, Tadi S, Kim Y . CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane. Cell Metab. 2012; 16(2):274-83. DOI: 10.1016/j.cmet.2012.06.012. View

12.

Kim Y, Joung K, Ryu M, Kim S, Kim H, Chung H . Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure. Diabetologia. 2015; 58(4):771-80. DOI: 10.1007/s00125-015-3506-y. View

13.

Kim K, Ryu D, Dongiovanni P, Ozcan L, Nayak S, Ueberheide B . Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis. Gastroenterology. 2017; 153(6):1568-1580.e10. PMC: 5705280. DOI: 10.1053/j.gastro.2017.08.039. View

14.

Segerstolpe A, Palasantza A, Eliasson P, Andersson E, Andreasson A, Sun X . Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes. Cell Metab. 2016; 24(4):593-607. PMC: 5069352. DOI: 10.1016/j.cmet.2016.08.020. View

15.

Kwon M, Koo B, Moon J, Kim Y, Park K, Kim N . Crif1 is a novel transcriptional coactivator of STAT3. EMBO J. 2008; 27(4):642-53. PMC: 2262042. DOI: 10.1038/sj.emboj.7601986. View

16.

Brouwers B, de Faudeur G, Osipovich A, Goyvaerts L, Lemaire K, Boesmans L . Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression. Cell Metab. 2014; 20(6):979-90. PMC: 5674787. DOI: 10.1016/j.cmet.2014.11.004. View

17.

Li D, Yuan Y, Tu H, Liang Q, Dai L . A protocol for islet isolation from mouse pancreas. Nat Protoc. 2009; 4(11):1649-52. DOI: 10.1038/nprot.2009.150. View

18.

Wikstrom J, Sereda S, Stiles L, Elorza A, Allister E, Neilson A . A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets. PLoS One. 2012; 7(5):e33023. PMC: 3351473. DOI: 10.1371/journal.pone.0033023. View

19.

Dominguez V, Raimondi C, Somanath S, Bugliani M, Loder M, Edling C . Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells. J Biol Chem. 2010; 286(6):4216-25. PMC: 3039383. DOI: 10.1074/jbc.M110.200295. View

20.

Solimena M, Schulte A, Marselli L, Ehehalt F, Richter D, Kleeberg 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. Diabetologia. 2017; 61(3):641-657. PMC: 5803296. DOI: 10.1007/s00125-017-4500-3. View