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Our objectives were to investigate the ability of chondrocytes to upregulate mitochondrial respiration when challenged with a nutrient stress and determine the effect on mediators of chondrocyte oxidative homeostasis.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>Primary bovine chondrocytes were isolated and cultured in alginate beads. Mitochondrial respiration was stimulated by culturing cells with galactose-supplemented media for a period of 1 or 5\u00a0days. Metabolic flexibility was assessed by measuring metabolite and enzymatic biomarkers of glycolytic and mitochondrial metabolism. Oxidative homeostasis was assessed by measuring (1) cellular glutathione content and redox homeostasis, (2) rates of nitric oxide and superoxide production, and (3) the abundance and activity of cellular anti-oxidant proteins, especially the mitochondrial isoform of superoxide dismutase (SOD2). The regulatory role of hypoxia-inducible factor 2\u03b1 (HIF-2\u03b1) in mediating the metabolic and redox responses was evaluated by chemical stabilization with cobalt chloride (CoCl<jats:sub>2<\/jats:sub>).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>After 5\u00a0days of galactose culture, lactate production and lactate dehydrogenase activity were reduced by 92% (<jats:italic>P<\/jats:italic> &lt;0.0001) and 28% (<jats:italic>P<\/jats:italic>\u2009=\u20090.051), respectively. Conversely, basal oxygen consumption increased 35% (<jats:italic>P<\/jats:italic>\u2009=\u20090.042) without increasing mitochondrial content. Glutathione redox homeostasis was unaffected by galactose culture. However, the production of nitric oxide and superoxide and the expression and activity of SOD2 were significantly reduced after 5\u00a0days in galactose culture. Nuclear protein expression and gene expression of HIF-2\u03b1, a transcription factor for SOD2, were significantly downregulated (more than twofold; <jats:italic>P<\/jats:italic> &lt;0.05) with galactose culture. CoCl<jats:sub>2<\/jats:sub>-mediated stabilization of HIF-2\u03b1 during the initial galactose response phase attenuated the reduction in SOD2 (<jats:italic>P<\/jats:italic>\u2009=\u20090.028) and increased cell death (<jats:italic>P<\/jats:italic>\u2009=\u20090.003).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>Chondrocyte metabolic flexibility promotes cell survival during a nutrient stress by upregulating mitochondrial respiration and reducing the rate of reactive nitrogen and oxygen species production. These changes are coupled to a substantial reduction in the expression and activity of the mitochondrial anti-oxidant SOD2 and its pro-catabolic transcription factor HIF-2\u03b1, suggesting that an improved understanding of physiologic triggers of chondrocyte metabolic flexibility may provide new insight into the etiology of OA.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/s13075-015-0566-9","type":"journal-article","created":{"date-parts":[[2015,3,9]],"date-time":"2015-03-09T18:43:57Z","timestamp":1425926637000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Mitochondrial respiration and redox coupling in articular chondrocytes"],"prefix":"10.1186","volume":"17","author":[{"given":"Rachel S","family":"Lane","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Matsuzaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kinter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M","family":"Humphries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,10]]},"reference":[{"key":"566_CR1","volume-title":"Biology of cartilage cells","author":"RA Stockwell","year":"1979","unstructured":"Stockwell RA. 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