The mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes
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ABSTRACT:
PROVIDER: PRJNA706909 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondria are principal metabolic organelles that are increasingly unveiled as immune regulators. However, it is currently not known whether mitochondrial-encoded peptides modulate T cells to induce changes in phenotype and function. Here, we found that MOTS-c prevented autoimmune β-cell destruction via phenotypical and functional changes of T cells in NOD mice, a type 1 diabetes (T1D) animal model. MOTS-c ameliorated the development of hyperglycemia and reduced islet-infiltrating immune cells. Furthermore, adoptive transfer of T cells from MOTS-c-treated NOD mice significantly decreased the incidence of diabetes in NOD-SCID mice. Metabolic and genomic analysis revealed that MOTS-c modulated T cell phenotype and function by regulating TCR/mTORC1 pathway. We observed that T1D patients had a lower serum MOTS-c level than healthy controls. Furthermore, MOTS-c reduced T cell activation by alleviating T cells from the glycolytic stress in T1D patients suggesting a potential therapeutic implication. Our findings indicate that the MOTS-c acts as a regulator of T cell phenotype and function in autoimmune diabetes.
2021-03-06 | GSE168324 | GEO
Project description:Mitochondria are principal metabolic organelles that are increasingly unveiled as immune regulators. However, it is currently not known whether mitochondrial-encoded peptides modulate T cells to induce changes in phenotype and function. In this study, we found that MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) prevented autoimmune β cell destruction by targeting T cells in non-obese diabetic (NOD) mice. MOTS-c ameliorated the development of hyperglycemia and reduced islet-infiltrating immune cells. Furthermore, adoptive transfer of T cells from MOTS-c-treated NOD mice significantly decreased the incidence of diabetes in NOD-severe combined immunodeficiency (SCID) mice. Metabolic and genomic analyses revealed that MOTS-c modulated T cell phenotype and function by regulating T cell receptor (TCR)/mTOR complex 1 (mTORC1) signaling. Type 1 diabetes (T1D) patients had a lower serum MOTS-c level than did healthy controls. Furthermore, MOTS-c reduced T cell activation by alleviating T cells from the glycolytic stress in T1D patients, suggesting therapeutic potential. Our findings indicate that MOTS-c regulates the T cell phenotype and suppresses autoimmune diabetes.
| S-EPMC10083145 | biostudies-literature
Project description:Whole population RNASeq of pancreatic islet macrophages during autoimmune diabetes progression.
2020-03-27 | GSE141782 | GEO
Project description:Joint destruction is the major clinic burden in patients with rheumatoid arthritis (RA). It is unclear, though, how this autoimmune disease progresses to the point of deterioration of the joint. Here, we report that in a mouse model of RA the upregulation of TLR2 expression and its a(2,3) sialylation in RANK+ myeloid monocytes mediate the transition from autoimmunity to osteoclast fusion and bone resorption, resulting in joint destruction. The expression of a(2,3) sialyltransferases were significantly increased in RANK+TLR2+ myeloid monocytes, and their inhibition or treatment with a TLR2 inhibitor blocked osteoclast fusion. Notably, analysis of our single-cell RNA-sequencing (scRNA-seq) libraries generated from RA mice revealed a novel RANK+TLR2- subset that negatively regulated osteoclast fusion. Importantly, the RANK+TLR2+ subset was significantly diminished with the treatments. Moreover, the RANK+TLR2- subset could differentiate into a TRAP+ osteoclast lineage, but the resulting cells did not fuse to form osteoclasts. Our scRNA-seq data showed that Maf is highly expressed in the RANK+TLR2- subset, and the a(2,3) sialyltransferase inhibitor induced Maf expression in the RANK+TLR2+ subset. The identification of a RANK+TLR2- subset provides a potential explanation for TRAP+ mononuclear cells in bone and their anabolic activity. Further, TLR2 expression and its a(2,3) sialylation in the RANK+ myeloid monocytes could be effective targets to prevent autoimmune-mediated joint destruction.
2023-05-24 | GSE221704 | GEO
Project description:RANK+TLR2+ Myeloid Subpopulation Converts Autoimmune to Joint Destruction in Rheumatoid Arthritis
| PRJNA915396 | ENA
Project description:Type 1 diabetes is an autoimmune destruction of pancreatic islet beta cell disease, and it is important to find new alternative source of the islet beta cells to replace the damaged cells. Human embryonic stem (hES) cells possess unlimited self-renewal and pluripotency and thus have the potential to provide an unlimited supply of different cell types for tissue replacement. The hES-T3 cells with normal female karyotype were first differentiated into embryoid bodies and then induced to generate the pancreatic islet-like cell clusters, which expressed pancreatic islet cell-specific markers of insulin, glucagon and somatostatin. The expression profiles of microRNAs and mRNAs from the pancreatic islet-like cell clusters were further analyzed and compared with those of undifferentiated hES-T3 cells and differentiated embryoid bodies. MicroRNAs negatively regulate the expression of protein-coding mRNAs. The pancreatic islet-like cell clusters were found to exhibit very high expression of microRNAs miR-186, miR-199a and miR-339, which down-regulated the expression of LIN28, PRDM1, CALB1, GCNT2, RBM47, PLEKHH1, RBPMS2 and PAK6. Therefore, these microRNAs are very likely to play important regulatory roles in the differentiation of pancreatic islet cells and early embryonic development. In this investigation, both miRNA and mRNA expression profiles from the pancreatic islet-like cell clusters differentiated from hES-T3 cells (T3pi) were quantitatively determined and compared with those of undifferentiated hES-T3 cells grown on mouse embryonic fibroblast (MEF) feeder (T3ES) and embryoid bodies differentiated from hES-T3 cells (T3EB). Several target genes of pancreatic islet cell-specific miRNAs were identified. ***This submission represents the mRNA expression component of the study only***
2010-09-29 | E-GEOD-14503 | biostudies-arrayexpress
Project description:Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The recent identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA that yield bioactive peptides. Here we report the identification of a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c) that regulates insulin sensitivity and metabolic homeostasis. MOTS-c is detected in various tissues and in circulation in an age-dependent manner. Its primary target organ appears to be the skeletal muscle and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, causing a significant accumulation of AICAR levels concomitantly with AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may be more actively engaged in regulating metabolic homeostasis than previously recognized, through the production of peptides encoded within its genome that act at the cellular and organismal level. Human embryonic kidney cells (HEK293 cell line) were cultured in 10-cm dishes in 7 mL of phenol-free DMEM supplemented with 10% FBS and incubated with water (controls) or the 16-amino-acid peptide mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c, 10 uM) for 4 or 72 hours prior to RNA extraction.
2015-03-07 | E-GEOD-65068 | biostudies-arrayexpress
Project description:An early islet transcriptional signature drives local inflammation in autoimmune diabetes
| PRJNA839778 | ENA
Project description:Whole population RNASeq of pancreatic islet macrophages during autoimmune diabetes progression
| PRJNA594721 | ENA
Project description:Type 1 diabetes is an autoimmune destruction of pancreatic islet beta cell disease, and it is important to find new alternative source of the islet beta cells to replace the damaged cells. Human embryonic stem (hES) cells possess unlimited self-renewal and pluripotency and thus have the potential to provide an unlimited supply of different cell types for tissue replacement. The hES-T3 cells with normal female karyotype were first differentiated into embryoid bodies and then induced to generate the pancreatic islet-like cell clusters, which expressed pancreatic islet cell-specific markers of insulin, glucagon and somatostatin. The expression profiles of microRNAs and mRNAs from the pancreatic islet-like cell clusters were further analyzed and compared with those of undifferentiated hES-T3 cells and differentiated embryoid bodies. MicroRNAs negatively regulate the expression of protein-coding mRNAs. The pancreatic islet-like cell clusters were found to exhibit very high expression of microRNAs miR-186, miR-199a and miR-339, which down-regulated the expression of LIN28, PRDM1, CALB1, GCNT2, RBM47, PLEKHH1, RBPMS2 and PAK6. Therefore, these microRNAs are very likely to play important regulatory roles in the differentiation of pancreatic islet cells and early embryonic development.
2010-09-30 | GSE14503 | GEO