Targeting Parkin-regulated Metabolomic Change in Cartilage in the Treatment of Osteoarthritis

Overview

Journal iScience

Publisher Cell Press

Date 2024 Sep 2

PMID 39220257

Authors

Yiyang Ma

Yidan Pang

Ruomu Cao

Zhikai Zheng

Kaiwen Zheng

Yucheng Tian

Xiaoyuan Peng

Delin Liu

Dajiang Du

Lin Du

Zhigang Zhong

Lufeng Yao

Changqing Zhang

Junjie Gao

Affiliations

Soon will be listed here.

Abstract

Articular cartilage degeneration may lead to osteoarthritis (OA) during the aging process, but its underlying mechanism remains unknown. Here, we found that chondrocytes exhibited an energy metabolism shift from glycolysis to oxidative phosphorylation (OXPHOS) during aging. Parkin regulates various cellular metabolic processes. Reprogrammed cartilage metabolism by Parkin ablation decreased OXPHOS and increased glycolysis, with ameliorated aging-related OA. Metabolomics analysis indicated that lauroyl-L-carnitine (LLC) was decreased in aged cartilage, but increased in Parkin-deficient cartilage. , LLC improved the cartilage matrix synthesis of aged chondrocytes. , intra-articular injection of LLC in mice with anterior cruciate ligament transaction (ACLT) ameliorated OA progression. These results suggest that metabolic changes are regulated by Parkin-impaired cartilage during aging, and targeting this metabolomic changes by supplementation with LLC is a promising treatment strategy for ameliorating OA.

References

Lane R, Fu Y, Matsuzaki S, Kinter M, Humphries K, Griffin T . Mitochondrial respiration and redox coupling in articular chondrocytes. Arthritis Res Ther. 2015; 17:54. PMC: 4384316. DOI: 10.1186/s13075-015-0566-9. View

He Y, Ji Z, Gong Y, Fan L, Xu P, Chen X . Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation. Cell Rep. 2023; 42(2):112033. DOI: 10.1016/j.celrep.2023.112033. View

Molnar V, Matisic V, Kodvanj I, Bjelica R, Jelec Z, Hudetz D . Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis. Int J Mol Sci. 2021; 22(17). PMC: 8431625. DOI: 10.3390/ijms22179208. View

Eiyama A, Okamoto K . PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol. 2015; 33:95-101. DOI: 10.1016/j.ceb.2015.01.002. View

Shet K, Siddiqui S, Yoshihara H, Kurhanewicz J, Ries M, Li X . High-resolution magic angle spinning NMR spectroscopy of human osteoarthritic cartilage. NMR Biomed. 2011; 25(4):538-44. PMC: 3299852. DOI: 10.1002/nbm.1769. View

Zheng L, Zhang Z, Sheng P, Mobasheri A . The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. Ageing Res Rev. 2020; 66:101249. DOI: 10.1016/j.arr.2020.101249. View

Kim D, Song J, Jin E . BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation. Cells. 2021; 10(7). PMC: 8304751. DOI: 10.3390/cells10071839. View

Jian S, Chen W, Su Y, Su Y, Chuang T, Hsu S . Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis. Cell Death Dis. 2017; 8(5):e2779. PMC: 5520713. DOI: 10.1038/cddis.2017.192. View

Southan J, McHugh E, Walker H, Ismail H . Metabolic Signature of Articular Cartilage Following Mechanical Injury: An Integrated Transcriptomics and Metabolomics Analysis. Front Mol Biosci. 2021; 7:592905. PMC: 7773849. DOI: 10.3389/fmolb.2020.592905. View

10.

Ekholm-Reed S, Goldberg M, Schlossmacher M, Reed S . Parkin-dependent degradation of the F-box protein Fbw7β promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol. 2013; 33(18):3627-43. PMC: 3753862. DOI: 10.1128/MCB.00535-13. View

11.

Hwang S, Kim D, Choi G, An S, Hong Y, Suh Y . Parkin suppresses c-Jun N-terminal kinase-induced cell death via transcriptional regulation in Drosophila. Mol Cells. 2010; 29(6):575-80. DOI: 10.1007/s10059-010-0068-1. View

12.

Xu L, Wu Z, He Y, Chen Z, Xu K, Yu W . MFN2 contributes to metabolic disorders and inflammation in the aging of rat chondrocytes and osteoarthritis. Osteoarthritis Cartilage. 2020; 28(8):1079-1091. DOI: 10.1016/j.joca.2019.11.011. View

13.

Pritzker K, Gay S, Jimenez S, Ostergaard K, Pelletier J, Revell P . Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage. 2005; 14(1):13-29. DOI: 10.1016/j.joca.2005.07.014. View

14.

Ji Q, Zheng Y, Zhang G, Hu Y, Fan X, Hou Y . Single-cell RNA-seq analysis reveals the progression of human osteoarthritis. Ann Rheum Dis. 2018; 78(1):100-110. PMC: 6317448. DOI: 10.1136/annrheumdis-2017-212863. View

15.

Correia-Melo C, Ichim G, Tait S, Passos J . Depletion of mitochondria in mammalian cells through enforced mitophagy. Nat Protoc. 2016; 12(1):183-194. DOI: 10.1038/nprot.2016.159. View

16.

Wang X, Winter D, Ashrafi G, Schlehe J, Liang Wong Y, Selkoe D . PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell. 2011; 147(4):893-906. PMC: 3261796. DOI: 10.1016/j.cell.2011.10.018. View

17.

Zhou S, Cui Z, Urban J . Factors influencing the oxygen concentration gradient from the synovial surface of articular cartilage to the cartilage-bone interface: a modeling study. Arthritis Rheum. 2004; 50(12):3915-24. DOI: 10.1002/art.20675. View

18.

Gong Y, Tang N, Liu P, Sun Y, Lu S, Liu W . Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells. Autophagy. 2021; 18(7):1503-1521. PMC: 9298456. DOI: 10.1080/15548627.2021.1990515. View

19.

Jeon O, Kim C, Laberge R, Demaria M, Rathod S, Vasserot A . Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017; 23(6):775-781. PMC: 5785239. DOI: 10.1038/nm.4324. View

20.

Dai K, Radin D, Leonardi D . PINK1 depletion sensitizes non-small cell lung cancer to glycolytic inhibitor 3-bromopyruvate: Involvement of ROS and mitophagy. Pharmacol Rep. 2019; 71(6):1184-1189. DOI: 10.1016/j.pharep.2019.08.002. View