Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis

Harty, Len; Biniecka, Monika; O'Sullivan, Jacintha; Fox, Edward J.; Mulhall, Kevin; Veale, Douglas J.; Fearon, Ursula

doi:10.1136/annrheumdis-2011-200245

Cited by 76 publications

(59 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We studied the regulation of SIRT1 protein in vivo and found that SIRT1 levels were up regulated in the synovial tissues of RA smokers and correlated positively with increased leukocytic infiltration. Previously, it was shown that smokers respond less to therapies with disease modifying anti-rheumatic drugs and had higher levels of the chemokine MIP-1α [35]. The same study showed that CSE induces chemotaxis in vitro.…”

Section: Discussionsupporting

confidence: 50%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNF, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA. KEY MESSAGES: SIRT1 is upregulated by TNF but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF. AbstractRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study we investigated the regulation, expression and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract.Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF, but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can t...

show abstract

Section: Discussionsupporting

confidence: 50%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

View full text Add to dashboard Cite

show abstract

“…28 This quantitative PCR-based approach enables precise determination of mutation frequencies following exhaustive digestion of all wild type (non-mutant) sequences by the restriction enzyme Taq-I. Mitochondrial DNA was extracted using a previously reported protocol.…”

Section: Mitochondrial Random Mutation Capture Assaymentioning

confidence: 99%

“…Mitochondrial DNA was extracted using a previously reported protocol. 28 Following extraction, 10 μg of mtDNA was digested with 100 units of Taq αI restriction enzyme (New England Biolabs), 1× bovine serum albumin and a Taq αI-specific digestion buffer (10 mM Tris HCl, 10 mM MgCl 2 , 100 mM NaCl ( pH 8.4)) for 10 h, with 100 units of Taq-αI added to the reaction mixture every hour. PCR amplification was performed in 25 μL reaction mixtures containing 12.5 μL 2×SYBR Green Brilliant Mastermix (Stratagene), 0.1 μL uracil DNA glycosylase (New England Biolabs), 0.7 μL forward and reverse primers (10 pM/μL; DNA oligonucleotide (IDT)) and 6.7 μL H 2 O.…”

Section: Mitochondrial Random Mutation Capture Assaymentioning

confidence: 99%

“…25 Furthermore, hypoxia induces glucose transporters GLUT1 and GLUT3 in articular chondrocytes, 26 and several glycolytic enzymes in cartilage explants. 27 We have previously shown increased mitochondrial DNA mutation frequency and mitochondrial dysfunction in the RA joint, 28 which is associated with oxidative stress, angiogenesis, proinflammatory cytokines and activation of the NLRP3 inflammasome. [29][30][31][32][33] Furthermore, in RA, studies have shown increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/Nox2 in circulating leucocytes and synovium, 34 demonstrated altered expression of 6-phosphofructo-2kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) in naive CD4T cells, 35 and shown synovial deficiency of cytochrome C oxidase.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dysregulated bioenergetics: a key regulator of joint inflammation

et al. 2016

View full text Add to dashboard Cite

ObjectivesThis study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation.MethodsPrimary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).ResultsDMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions.ConclusionsHypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.

show abstract

“…For instance, mitochondrial dysfunction contributes to cell growth, tumorigenesis and inhibition of apoptosis and it is not surprising that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways. [6][7][8][9][10] Other mitochondria-related diseases include a number of genetic or acquired diseases, such as diabetes, 11 cardiologic, 12 vascular 13 and haematologic diseases, 14 15 Parkinson's disease, 16 Alzheimer's disease, 17 amyotrophic lateral sclerosis, 18 multiple sclerosis, 19 20 epilepsy, 21 22 and autistic spectrum disorders, 23 24 ataxia-telangiectasia, [25][26][27] Bloom syndrome, 28 29 Down syndrome, 30-32 psoriasis 33 34 and rheumatoid arthritis, [36][37][38] Due to the unmet demand for mitochondrial diseases, increasing interest in mitochondria-specific targeting has lead to the emergence of "Mitochondrial Medicine" as a new field of biomedical research.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeted Nanoparticles: A Promising Drug Delivery System

Liao¹,

Feng²

2016

j nanosci nanotechnol

View full text Add to dashboard Cite

A variety of diseases including neurodegenerative, neuromuscular diseases, diabetes, obesity and cancer are considered to be caused by mitochondrial dysfunction. Efficient delivery of therapeutic agents to mitochondria is necessary to treat these diseases. In the past decade, mitochondria targeted nanoparticles have been shown to be a promising deliver system. In this review, functionalized nanosystems targeting mitochondria are discussed. More efforts are needed to bring these novel nanosystems from bench top to bed side.

show abstract

Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis

Abstract: High mitochondrial mutations are strongly associated with synovial inflammation showing a direct link between mitochondrial mutations and key proinflammatory pathways.

Cited by 76 publications

References 42 publications

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

Dysregulated bioenergetics: a key regulator of joint inflammation

Mitochondria-Targeted Nanoparticles: A Promising Drug Delivery System

Contact Info

Product

Resources

About