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Title: Mitochondrial dysfunction and oxidative stress in osteoarthritis
Author: Gavriilidis, Christos
ISNI:       0000 0004 2737 9487
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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Mitochondria are considered the powerhouse of the cell being the major site of ATP production but in addition to this function they also regulate ROS production and inhibition, calcium handling and apoptosis. Previous studies have reported a downregulation in the levels of superoxide dismutase 2 (SOD2), an inhibitor of mitochondrial superoxide (O2--), in osteoarthritic (OA) hip cartilage compared to that from healthy joints (neck of femur fracture; NOF). This finding provides the opportunity to characterise the functional effects of SOD2 downregulation in OA in the context of oxidative damage and mitochondrial dysfunction. SOD2 depletion increased the mitochondrial O2-- levels in human articular chondrocytes (HAC). Measurement of lipid peroxidation levels in OA and NOF cartilage showed that OA cartilage has higher levels of lipid peroxidation compared to NOF. SOD2 depletion in a chondrosarcoma cell-line, SW1353, also led to a significant increase in lipid peroxidation levels. Additionally, SOD2 depletion led to a significant increase in mtDNA strand breaks in SW1353 cells although there was no difference detected in OA compared to NOF mtDNA. However, large-scale mtDNA deletions were identified in OA cartilage and other OA joint tissues but the low levels of mutated mtDNA observed were not considered to be pathologically relevant. Mitochondrial respiratory function was also determined in OA and NOF isolated chondrocytes. OA chondrocytes showed less spare respiratory capacity (SRC), higher non-phosphorylating respiration and higher proton leak compared to NOF. SOD2-depleted HAC also showed a lower SRC and higher proton leak. Additionally, HAC demonstrated a very low mitochondrial/glycolysis ratio, suggesting that HAC are highly glycolytic cells. SOD2 depletion caused depolarization of the Δψm. NLRX1, a mitochondrially localised gene involved in innate immunity signalling was also identified to regulate basal levels of matrix metalloproteinase 13 (MMP-13) and double stranded RNA- induced ROS levels in chondrocytes. These findings suggest that SOD2 depletion in chondrocytes leads to oxidative damage and mitochondrial dysfunction caused by increasing ROS levels and can potentially lead towards alterations in cell signalling pathways, cellular dysfunction and cartilage degradation.
Supervisor: Not available Sponsor: Arthritis Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available