Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.

Hdl Handle:
http://hdl.handle.net/10147/207698
Title:
Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.
Authors:
Biniecka, Monika; Fox, Edward; Gao, Wei; Ng, Chin Teck; Veale, Douglas J; Fearon, Ursula; O'Sullivan, Jacintha
Affiliation:
Dublin Academic Medical Centre, St. Vincent's University Hospital, and The Conway, Institute of Biomolecular and Biomedical Research, University College Dublin,, Dublin, Ireland.
Citation:
Arthritis Rheum. 2011 Aug;63(8):2172-82. doi: 10.1002/art.30395.
Journal:
Arthritis and rheumatism
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207698
DOI:
10.1002/art.30395
PubMed ID:
21484771
Abstract:
OBJECTIVE: To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels. METHODS: Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO(2)) were measured at arthroscopy using a Licox probe. Synovial expression of lipid peroxidation (4-hydroxynonenal [4-HNE]) and mitochondrial cytochrome c oxidase subunit II (CytcO II) deficiency were assessed by immunohistochemistry. In vitro levels of mtDNA point mutations, reactive oxygen species (ROS), mitochondrial membrane potential, and markers of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine [8-oxodG]) and lipid peroxidation (4-HNE) were determined in human synoviocytes under normoxia and hypoxia (1%) in the presence or absence of superoxide dismutase (SOD) or N-acetylcysteine (NAC) or a hydroxylase inhibitor (dimethyloxalylglycine [DMOG]). Patients were categorized according to their in vivo tPO(2) level (<20 mm Hg or >20 mm Hg), and mtDNA point mutations, immunochemistry features, and stress markers were compared between groups. RESULTS: The median tPO(2) level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P = 0.05) and with higher synovial 4-HNE cytoplasmic expression (P = 0.04). Synovial expression of CytcO II correlated with in vivo tPO(2) levels (P = 0.03), and levels were lower in patients with tPO(2) <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC. CONCLUSION: These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.
Language:
eng
MeSH:
Anoxia/*genetics/metabolism; Arthritis, Psoriatic/genetics/*metabolism; Arthritis, Rheumatoid/genetics/*metabolism; Cells, Cultured; Humans; Inflammation/genetics/metabolism; Mitochondria/genetics/*metabolism; *Mutagenesis; Oxidative Stress/genetics; Reactive Oxygen Species/metabolism; Synovial Fluid/metabolism; Synovial Membrane/metabolism
ISSN:
1529-0131 (Electronic); 0004-3591 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorBiniecka, Monikaen_GB
dc.contributor.authorFox, Edwarden_GB
dc.contributor.authorGao, Weien_GB
dc.contributor.authorNg, Chin Tecken_GB
dc.contributor.authorVeale, Douglas Jen_GB
dc.contributor.authorFearon, Ursulaen_GB
dc.contributor.authorO'Sullivan, Jacinthaen_GB
dc.date.accessioned2012-02-01T10:35:16Z-
dc.date.available2012-02-01T10:35:16Z-
dc.date.issued2012-02-01T10:35:16Z-
dc.identifier.citationArthritis Rheum. 2011 Aug;63(8):2172-82. doi: 10.1002/art.30395.en_GB
dc.identifier.issn1529-0131 (Electronic)en_GB
dc.identifier.issn0004-3591 (Linking)en_GB
dc.identifier.pmid21484771en_GB
dc.identifier.doi10.1002/art.30395en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207698-
dc.description.abstractOBJECTIVE: To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels. METHODS: Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO(2)) were measured at arthroscopy using a Licox probe. Synovial expression of lipid peroxidation (4-hydroxynonenal [4-HNE]) and mitochondrial cytochrome c oxidase subunit II (CytcO II) deficiency were assessed by immunohistochemistry. In vitro levels of mtDNA point mutations, reactive oxygen species (ROS), mitochondrial membrane potential, and markers of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine [8-oxodG]) and lipid peroxidation (4-HNE) were determined in human synoviocytes under normoxia and hypoxia (1%) in the presence or absence of superoxide dismutase (SOD) or N-acetylcysteine (NAC) or a hydroxylase inhibitor (dimethyloxalylglycine [DMOG]). Patients were categorized according to their in vivo tPO(2) level (<20 mm Hg or >20 mm Hg), and mtDNA point mutations, immunochemistry features, and stress markers were compared between groups. RESULTS: The median tPO(2) level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P = 0.05) and with higher synovial 4-HNE cytoplasmic expression (P = 0.04). Synovial expression of CytcO II correlated with in vivo tPO(2) levels (P = 0.03), and levels were lower in patients with tPO(2) <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC. CONCLUSION: These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.en_GB
dc.language.isoengen_GB
dc.subject.meshAnoxia/*genetics/metabolismen_GB
dc.subject.meshArthritis, Psoriatic/genetics/*metabolismen_GB
dc.subject.meshArthritis, Rheumatoid/genetics/*metabolismen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshHumansen_GB
dc.subject.meshInflammation/genetics/metabolismen_GB
dc.subject.meshMitochondria/genetics/*metabolismen_GB
dc.subject.mesh*Mutagenesisen_GB
dc.subject.meshOxidative Stress/geneticsen_GB
dc.subject.meshReactive Oxygen Species/metabolismen_GB
dc.subject.meshSynovial Fluid/metabolismen_GB
dc.subject.meshSynovial Membrane/metabolismen_GB
dc.titleHypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.en_GB
dc.contributor.departmentDublin Academic Medical Centre, St. Vincent's University Hospital, and The Conway, Institute of Biomolecular and Biomedical Research, University College Dublin,, Dublin, Ireland.en_GB
dc.identifier.journalArthritis and rheumatismen_GB
dc.description.provinceLeinster-

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