Fig. 3

The relationship between energy shortage and chondrocyte senescence. Energy deficiency caused by damaged mitochondria activates AMPK, and SIRTs including SIRT1, SIRT3 and SIRT6. SIRT1 protects cartilage by promoting the transcription of Sox9 and collagen 2. Several factors such miR-34a and leptin inhibit SIRT1 and exacerbate chondrocyte senescence and cartilage damage. Damaged mitochondria are eliminated by p62-mediated autophagy. Activated in an inflammatory environment, NF-κB promotes SASP factor transcription. SASP factors activate NF-κB in an autocrine manner, forming a positive feedback loop. Energy deficiency activates mTOR via AMPK. mTOR inhibits ZFP36L1 by activating MKK. ZFP36L1 and some miRNAs, such as miR-204 participate in the degradation of SASPs. Decreased NAD + /NADH also activates SIRT3 and SIRT6 in addition to SIRT1. SIRT3 deacetylates SOD2 and increases SOD2-specific activity, thus protecting chondrocytes against oxidative stress. SIRT6 can inhibit DNA damage and cellular senescence. SIRT, sirtuin; AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase; mTOR, mammalian target of rapamycin; ZFP36L1, ZFP36 ring finger protein like 1; SOD2, superoxide dismutase 2