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Updated: May 22, 2025

Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
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SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch

Yaoge Deng1,2, Mingzhuang Hou1,2, Yubin Wu1,2

  • 1Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.

Bone Research
|March 15, 2025
PubMed

Insights

This study reveals how mitochondrial quality control, involving PTEN-induced putative kinase 1 (PINK1) and SIRT3, protects cartilage from osteoarthritis (OA) by enhancing energy production and removing damaged mitochondria.

Area of Science:

  • Mitochondrial biology
  • Cellular homeostasis
  • Osteoarthritis research

Background:

  • Mitochondrial dysfunction and impaired mitophagy are implicated in osteoarthritis (OA).
  • The precise mechanisms regulating mitochondrial renewal and energy metabolism in chondrocytes during OA remain unclear.

Purpose of the Study:

  • To elucidate the role of the SIRT3-PINK1-PKM2 signaling axis in maintaining chondrocyte function and preventing cartilage degeneration in OA.
  • To investigate how mitochondrial homeostasis is regulated through mitophagy and metabolic reprogramming.

Main Methods:

  • Analysis of mitochondrial damage and mitophagy in OA chondrocytes.
  • Genetic manipulation of PINK1 and SIRT3 expression in cellular and animal models.
  • Investigation of protein-protein interactions and phosphorylation events (PINK1-PKM2).
  • Assessment of metabolic shifts and energy production.
  • Evaluation of joint integrity and motor function in a double-knockout mouse model.

Main Results:

  • OA chondrocytes exhibit mitochondrial damage and defective mitophagy.
  • Overexpression of PTEN-induced putative kinase 1 (PINK1) protected against cartilage degeneration by enhancing mitophagy.
  • PINK1 knockout exacerbated cartilage damage due to impaired mitophagy.
  • SIRT3 deacetylated PINK1, promoting mitophagy and cartilage anabolism.
  • PINK1 phosphorylated PKM2, maintaining its active tetrameric form, inhibiting nuclear translocation, and promoting a metabolic shift towards increased energy production.
  • The SIRT3-PINK1-PKM2 axis was crucial for maintaining joint structural integrity and improving motor function in mice.

Conclusions:

  • The SIRT3-PINK1-PKM2 axis is a key regulator of mitochondrial renewal and metabolic reprogramming in osteoarthritis.
  • Targeting this pathway offers a potential therapeutic strategy for preserving chondrocyte function and combating OA progression.

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