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Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor ? coactivator 1?.

ABSTRACT: The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?). Moreover, PGC-1? critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT-1/PGC-1? pathway.We assessed the expression and activity (phosphorylation) of AMPK?, SIRT-1, and PGC-1? in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]).Human knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPK? activity and decreased expression of SIRT-1, PGC-1?, TFAM, NRF-1, and NRF-2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol-cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin-1?. Finally, activation of AMPK by A-769662 increased PGC-1? expression via SIRT-1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes.Mitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM-mediated activation of the AMPK/SIRT-1/PGC-1? pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4519411 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α.

Wang Yun Y Zhao Xianling X Lotz Martin M Terkeltaub Robert R Liu-Bryan Ru R

Arthritis & rheumatology (Hoboken, N.J.) 20150501 8

<h4>Objective</h4>The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, PGC-1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test t ...[more]

PMID: 25940958

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Project description:BackgroundDespite advances in diagnosing and treating chronic heart failure (HF), the underlying mechanisms in different HF phenotypes remain unclear. Mitochondrial energy metabolism is crucial in HF etiology. Our study aimed to explore the value of metabolic-associated biomarker peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in identifying different HF phenotypes.MethodsA total of 172 participants were enrolled in the Affiliated Hospital of Xuzhou Medical University and were subsequently divided into four groups based on the European Society of Cardiology HF management guideline: the non-HF control (Control, N = 46), heart failure with reduced ejection fraction (HFrEF, N = 54), heart failure with mildly reduced ejection fraction (HFmrEF, N = 22), and heart failure with preserved ejection fraction (HFpEF, N = 50) groups. Each participant's baseline data were recorded, blood samples were taken, and echocardiography was conducted. The level of PGC1α expression was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The receiver operative characteristics (ROC) curve was further established in the four groups to assess the diagnostic value for overall HF and each HF phenotype with the calculation of the area under the curve (AUC) and 95% confidence interval (CI).ResultsPGC1α expression was significantly increased in HF patients (315.0 ± 69.58 nmol/L) compared to non-HF participants (233.3 ± 32.69 nmol/L). Considering different HF phenotypes, PGC1α expression was considerably higher in the HFmrEF group (401.6 ± 45.1 nmol/L)than in the other two phenotypes (299.5 ± 62.27 nmol/L for HFrEF and 293.5 ± 56.37 nmol/L for HFpEF, respectively).Furthermore, the AUCs of PGC1α in overall HF and each HF phenotype were all over 0.8, showing the ideal diagnostic value. Additionally, we provided the cut-off criteria for clinical use, which needs further validation. There was no significant correlation between PGC1α and N-terminal (NT)-prohormone B-type natriuretic peptide (BNP)/blood glucose, suggesting that PGC1α might exert a unique function in HF yet in a different pattern.ConclusionWe discovered that PGC1α could be used as a potential biomarker for differentiating HF patients from those without HF and for distinguishing HFmrEF from HFrEF and HFpEF.

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Dataset Information

Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor ? coactivator 1?.

Publications

Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α.

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