Faculty, Staff and Student Publications

Language

English

Publication Date

9-9-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2426992122

PMID

40892916

PMCID

PMC12435279

PubMedCentral® Posted Date

9-2-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Animals, Osteoarthritis, Chondrocytes, Mitochondria, Mice, GTP Phosphohydrolases, Endoplasmic Reticulum, Sirtuin 3, Humans, Mitochondrial Proteins, Endoplasmic Reticulum Stress, Cartilage, Articular, Mitochondrial Dynamics, Male, Mice, Inbred C57BL, osteoarthritis, mitochondrial dynamics, posttranslational modifications, endoplasmic reticulum, extracellular vesicles

Comments

This article has been corrected. See Proc Natl Acad Sci U S A. 2026 Jan 29;123(5):e2600337123.

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.