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

Abstract

Diabetes: A mitochondrial mechanism underlying impaired insulin release Disruptions in the mitochondrial protein synthesis machinery give rise to metabolic disturbances that lay the foundation for type 2 diabetes. As physiological glucose levels rise, the energy-generating machinery of the mitochondria responds with increased activity, which stimulates insulin secretion. Many proteins responsible for mitochondrial metabolism are produced by ribosomes within this cellular organelle. Researchers led by Hyun Jin Kim and Minho Shong at Chungnam National University, Daejon, South Korea, have determined that mutations affecting a mitochondrial ribosomal protein called CRIF1 can lead to impaired insulin release. Mice with reduced CRIF1 were initially healthy, but as they aged, exhibited signs of impaired pancreatic function similar to those seen in patients with early-stage diabetes. This process was accelerated by consumption of a high-fat diet, and the researchers propose that this mechanism may be directly relevant to human disease. 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 beta-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 beta-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1(beta+/-) mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased beta-cell mass associated with higher expression of Reg family genes. However, Crif1(beta+/-) 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.