Proceedings of the National Academy of Sciences of the United States of AmericaSep 2, 2025

Restoring communication between energy and protein-processing parts of cells to treat osteoarthritis

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Updated Jan 20, 2026

Abstract

Loss of mitofusin-2 (MFN2) expression in chondrocytes leads to impaired mitochondrial function and cartilage degeneration in osteoarthritis.

Impaired mitochondrial function and disrupted cartilage matrix metabolism are linked to the loss of MFN2 in chondrocytes.
Sirtuin-3 (SIRT3) regulates MFN2 to restore mitochondrial dynamics and function.
SIRT3 prevents MFN2 degradation by directly deacetylating and indirectly deubiquitinating it.
MFN2 supports cellular health by maintaining mitochondrial-endoplasmic reticulum junctions and calcium ion balance.
Extracellular vesicles with MFN2 mRNA have shown potential to prevent cartilage degeneration in osteoarthritic mice.

Simplified

Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.

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Competing interests

Competing interests statement:The authors declare no competing interest.

PubMed

Restoring communication between energy and protein-processing parts of cells to treat osteoarthritis

Abstract

Full Text

Funding

Competing interests

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