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Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes

BACKGROUND: Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitoc...

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Autores principales: Torres, Alyssa, Kang, Sarah, Mahony, Christopher B., Cedeño, Martha, Oliveira, Patricia G., Fernandez-Bustamante, Marta, Kemble, Samuel, Laragione, Teresina, Gulko, Percio S., Croft, Adam P., Sanchez-Lopez, Elsa, Miyamoto, Shigeki, Guma, Monica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10389265/
https://www.ncbi.nlm.nih.gov/pubmed/37529037
http://dx.doi.org/10.3389/fimmu.2023.1103231
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author Torres, Alyssa
Kang, Sarah
Mahony, Christopher B.
Cedeño, Martha
Oliveira, Patricia G.
Fernandez-Bustamante, Marta
Kemble, Samuel
Laragione, Teresina
Gulko, Percio S.
Croft, Adam P.
Sanchez-Lopez, Elsa
Miyamoto, Shigeki
Guma, Monica
author_facet Torres, Alyssa
Kang, Sarah
Mahony, Christopher B.
Cedeño, Martha
Oliveira, Patricia G.
Fernandez-Bustamante, Marta
Kemble, Samuel
Laragione, Teresina
Gulko, Percio S.
Croft, Adam P.
Sanchez-Lopez, Elsa
Miyamoto, Shigeki
Guma, Monica
author_sort Torres, Alyssa
collection PubMed
description BACKGROUND: Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype. METHODS: HK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)–HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice. RESULTS: Cobalt chloride (CoCl(2)) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN. CONCLUSION: Our results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.
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spelling pubmed-103892652023-08-01 Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes Torres, Alyssa Kang, Sarah Mahony, Christopher B. Cedeño, Martha Oliveira, Patricia G. Fernandez-Bustamante, Marta Kemble, Samuel Laragione, Teresina Gulko, Percio S. Croft, Adam P. Sanchez-Lopez, Elsa Miyamoto, Shigeki Guma, Monica Front Immunol Immunology BACKGROUND: Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype. METHODS: HK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)–HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice. RESULTS: Cobalt chloride (CoCl(2)) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN. CONCLUSION: Our results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition. Frontiers Media S.A. 2023-07-17 /pmc/articles/PMC10389265/ /pubmed/37529037 http://dx.doi.org/10.3389/fimmu.2023.1103231 Text en Copyright © 2023 Torres, Kang, Mahony, Cedeño, Oliveira, Fernandez-Bustamante, Kemble, Laragione, Gulko, Croft, Sanchez-Lopez, Miyamoto and Guma https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Torres, Alyssa
Kang, Sarah
Mahony, Christopher B.
Cedeño, Martha
Oliveira, Patricia G.
Fernandez-Bustamante, Marta
Kemble, Samuel
Laragione, Teresina
Gulko, Percio S.
Croft, Adam P.
Sanchez-Lopez, Elsa
Miyamoto, Shigeki
Guma, Monica
Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
title Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
title_full Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
title_fullStr Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
title_full_unstemmed Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
title_short Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes
title_sort role of mitochondria-bound hk2 in rheumatoid arthritis fibroblast-like synoviocytes
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10389265/
https://www.ncbi.nlm.nih.gov/pubmed/37529037
http://dx.doi.org/10.3389/fimmu.2023.1103231
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