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1.
J Biol Chem ; 300(4): 107120, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38417794

ABSTRACT

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1ß cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1ß release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.


Subject(s)
Colitis, Ulcerative , Endoplasmic Reticulum , Inflammasomes , Macrophages , Membrane Proteins , Mitochondria , NLR Family, Pyrin Domain-Containing 3 Protein , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/pathology , Colitis, Ulcerative/genetics , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics , Mitochondria/metabolism , Mitochondria/pathology , Macrophages/metabolism , Macrophages/pathology , Inflammasomes/metabolism , Animals , Endoplasmic Reticulum/metabolism , Mice , Interleukin-1beta/metabolism , Interleukin-1beta/genetics , Male , Dextran Sulfate/toxicity
2.
Basic Res Cardiol ; 118(1): 46, 2023 11 03.
Article in English | MEDLINE | ID: mdl-37923788

ABSTRACT

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.


Subject(s)
Heart Failure , Animals , Mice , Rats , Cardiomegaly , DNA-Binding Proteins/metabolism , Heart Failure/metabolism , Mitochondria/metabolism , Muscle Proteins/genetics , Myocytes, Cardiac/metabolism , Protein Isoforms/metabolism , Protein Isoforms/pharmacology , RNA, Messenger/metabolism , RNA, Messenger/pharmacology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Transcription Factors/metabolism , Transcription Factors/pharmacology
3.
Matrix Biol ; 112: 72-89, 2022 09.
Article in English | MEDLINE | ID: mdl-35964866

ABSTRACT

Intrarenal extracellular matrix production or kidney fibrosis is a prevalent feature of all forms of chronic kidney disease (CKD). The transforming growth factor-beta (TGFß) is believed to be a major driver of extracellular matrix production. Nevertheless, anti-TGFß therapies have consistently failed to reduce extracellular matrix production in CKD patients indicating the need for novel therapeutic strategies. We have previously shown that necroinflammation contributes to acute kidney injury. Here, we show that chronic/persistent necroinflammation drives intrarenal extracellular matrix production during CKD. We found that renal expression of receptor-interacting protein kinase-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) increases with the production of intrarenal extracellular matrix and declined kidney function in both humans and mice. Furthermore, we found that TGFß exposure induces the translocation of RIPK3 and MLKL to mitochondria resulting in mitochondrial dysfunction and ROS production. Mitochondrial ROS activates the serine-threonine kinase calcium/calmodulin-dependent protein kinases-II (CaMKII) that increases phosphorylation of Smad2/3 and subsequent production of alpha-smooth muscle actin (αSMA), collagen (Col) 1α1, etc. in response to TGFß during the intrarenal extracellular matrix production. Consistent with this, deficiency or knockdown of RIPK3 or MLKL as well as pharmacological inhibition of RIPK1, RIPK3, and CaMKII prevents the intrarenal extracellular matrix production in oxalate-induced CKD and unilateral ureteral obstruction (UUO). Together, RIPK1, RIPK3, MLKL, CaMKII, and Smad2/3 are molecular targets to inhibit intrarenal extracellular matrix production and preserve kidney function during CKD.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Renal Insufficiency, Chronic , Actins/metabolism , Animals , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Extracellular Matrix/metabolism , Humans , Mice , Mitochondria/metabolism , Oxalates/metabolism , Protein Kinases/metabolism , Reactive Oxygen Species/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/metabolism , Transforming Growth Factors/metabolism
6.
Diabetes Metab Syndr ; 13(4): 2653-2659, 2019.
Article in English | MEDLINE | ID: mdl-31405690

ABSTRACT

BACKGROUND: Metabolic syndrome (MS) increases the risk of heart disease, stroke, and other complications. AIM: The aim of this study was to assess the clinical and biochemical parameters of MS and its complications (cerebrovascular accidents, cardiovascular accidents, DN or chronic kidney disease (CKD) compared with healthy controls especially among the younger population in Northern India. MATERIAL AND METHODS: A total of 245 (healthy, MS and it's complicated) aged 18-70 years participated in the Open-Label, Single Centered; hospital-based random selection case-control comparative study. All anthropometric and biochemical assessment was done after proper consent. The metabolic syndrome was determined by IDF criteria. RESULTS: The key risk parameters in three groups i.e. Control, Metabolic syndrome, and Complicated was TG (96.5 ±â€¯46.9, 194.1 ±â€¯87.8, 148.0 ±â€¯102.2). LDL (91.2 ±â€¯27.2, 114.0 ±â€¯31.8, 69.1 ±â€¯42.5, BP (120.1 ±â€¯9.9, 139.3 ±â€¯13.3, 132.1 ±â€¯15.0) and high fasting glucose (81.1 ±â€¯13.7, 164.5 ±â€¯84.3, 138.0 ±â€¯74.5). The hs-CRP is also significantly increased in the complicated group. The subanalysis of data also indicates that younger middle age (36-55 years) group both male and female is obese, hypertensive, diabetic with lipid abnormality according to IDF criteria. CONCLUSION: The risk factors like high TG, low HDL, high BP, and high fasting glucose were found higher particularly in younger population which may lead to diagnosis & complications of diabetes, hypertension and lipid abnormality. Due to changing physiology in young and middle age population these individuals are moving towards metabolic syndrome easily and needs frequent monitoring, preventive checkups, and lifestyle changes to prevent complications.


Subject(s)
Biomarkers/analysis , Cardiovascular Diseases/etiology , Cerebrovascular Disorders/etiology , Diabetes Mellitus/etiology , Metabolic Syndrome/complications , Renal Insufficiency, Chronic/etiology , Adolescent , Adult , Aged , Anthropometry , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Case-Control Studies , Cerebrovascular Disorders/metabolism , Cerebrovascular Disorders/pathology , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Female , Follow-Up Studies , Humans , Lipids/analysis , Male , Middle Aged , Prognosis , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology , Young Adult
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