Mitochondrial biogenesis is impaired in osteoarthritic chondrocytes but reversible via peroxisome pr
The etiology of chondrocyte mitochondrial dysfunction in OA is incompletely understood. OA chondrocytes are deficient in active AMPK-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), metabolic biosensors that modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α. Moreover, PGC-1α critically mediates AMPK anti-catabolic activity in chondrocytes. Here, we tested the hypotheses that mitochondrial biogenesis is deficient in human OA chondrocytes, which functionally increases chondrocyte pro-catabolic responses, but is reversed by activation of the AMPK-SIRT1-PGC-1α pathway.
We studied human knee chondrocytes, human and mouse knee cartilages. We examined expression and activity (phosphorylation) of AMPKα, and SIRT1 and PGC-1α, and defined and compared mitochondrial content and functions including oxidative phosphorylation (OXPHOS) with expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A (TFAM), nuclear respiratory factors (NRFs)).
Human knee OA chondrocytes had decreased mitochondrial biogenesis capacity, linked to reduced AMPKα activity and decreased SIRT1, PGC-1α, TFAM, and NRF1,2 expression. Human knee OA and aged mouse knee cartilages had decreased TFAM and ubiquinol-cytochrome c reductase core protein I (UQCEC1), a subunit of mitochondrial complex III, in situ. Functionally, chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced pro-catabolic responses to IL-1β. Last, pharmacologic AMPK activation by A-769662 increased PGC-1α via SIRT1, and reversed impairments in mitochondrial biogenesis, OXPHOS, and intracellular ATP in human knee OA chondrocytes.
Mitochondrial biogenesis is deficient in human OA chondrocytes and this promotes chondrocyte pro-catabolic responses. Activation of the AMPK-SIRT1-PGC-1α pathway reverses these effects, mediated by TFAM, suggesting translational potential to limit OA progression. This article is protected by copyright. All rights reserved.
Mitochondrial biogenesis is impaired in osteoarthritic chondrocytes but reversible via peroxisome proliferator-activated receptor-γ coactivator 1α