Mitochondrial biogenesis is impaired in osteoarthritic chondrocytes but reversible via peroxisome pr

OBJECTIVE:

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.
METHODS:

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)).
RESULTS:

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.
CONCLUSIONS:

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.