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KMID : 0620920220540070932
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Experimental & Molecular Medicine
2022 Volume.54 No. 7 p.932 ~ p.945
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Mitoribosome insufficiency in β cells is associated with type 2 diabetes-like islet failure
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Hong Hyun-Jung
Joung Kyong-Hye
Kim Yong-Kyung
Choi Min-Jeong
Kang Seul-Gi
Kim Jung-Tae
Kang Yea-Eun
Chang Joon-Young
Moon Joon-Ho
Jun Sang-Mi
Ro Hyun-Joo
Lee Yu-Jeong
Kim Hyeong-Seok
Park Jae-Hyung
Kang Baeki E.
Jo Yun-Ju
Choi Hee-Jung
Ryu Dong-Ryeol
Lee Chul-Ho
Kim Ha-Il
Park Kyu-Sang
Kim Hyun-Jin
Shong Min-Ho
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Abstract
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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.
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KEYWORD
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Endocrine system and metabolic diseases, Pre-diabetes, Type 2 diabetes
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