<br>通过靶向 SIRT3-COX4I2 轴重编程线粒体呼吸链复合物可减缓骨关节炎进展,Advanced Science

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通过靶向 SIRT3-COX4I2 轴重编程线粒体呼吸链复合物可减缓骨关节炎进展
Advanced Science ( IF 14.3 ) Pub Date : 2023-01-22 , DOI: 10.1002/advs.202206144
Yijian Zhang _{1,

2} , Yang Liu _{1,

2} , Mingzhuang Hou _{1,

2} , Xiaowei Xia _{1,

2} , Junlin Liu _{1,

2} , Yong Xu ₂ , Qin Shi _{1,

2} , Zhongmin Zhang ₃ , Liang Wang ₄ , Yifan Shen ₅ , Huilin Yang _{1,

2} , Fan He _{1,

2} , Xuesong Zhu _{1,

2}

Affiliation

线粒体稳态对于软骨完整性非常重要，并且与骨关节炎 (OA) 的进展相关；然而，其根本机制尚不清楚。本研究旨在探讨线粒体脱乙酰化反应的作用以及OA发生的机制关系。在人类关节炎软骨和小鼠炎症软骨细胞中，沉默交配型信息调节 2 同源物 3 (SIRT3) 的表达与 OA 的严重程度呈负相关。整体 SIRT3 缺失加速了创伤后 OA 小鼠的病理表型，软骨细胞外基质塌陷、骨赘形成和滑膜巨噬细胞 M1 极化证明了这一点。从机制上讲，SIRT3 通过靶向和脱乙酰细胞色素 c 氧化酶亚基 4 亚型 2 (COX4I2) 来维持翻译后水平的线粒体稳态，从而防止 OA 进展。和厚朴酚激活 SIRT3 可恢复软骨代谢平衡并保护小鼠免受创伤后 OA 的发展。总的来说，线粒体 SIRT3 的缺失对于 OA 的发生至关重要，而 SIRT3 介导的 COX4I2 蛋白去乙酰化可以挽救 OA 受损的线粒体呼吸链功能，从而改善 OA 表型。在此，SIRT3的诱导为OA治疗提供了一种新的治疗候选者。

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Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3-COX4I2 Axis Attenuates Osteoarthritis Progression

Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression of osteoarthritis (OA); however, the underlying mechanisms are unknown. This study aims to investigate the role of mitochondrial deacetylation reaction and investigate the mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation with the severity of OA in both human arthritic cartilage and mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype in post-traumatic OA mice, as evidenced by cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1 polarization. Mechanistically, SIRT3 prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis at the post-translational level. The activation of SIRT3 by honokiol restores cartilage metabolic equilibrium and protects mice from the development of post-traumatic OA. Collectively, the loss of mitochondrial SIRT3 is essential for the development of OA, whereas SIRT3-mediated proteins deacetylation of COX4I2 rescues OA-impaired mitochondrial respiratory chain functions to improve the OA phenotype. Herein, the induction of SIRT3 provides a novel therapeutic candidate for OA treatment.

更新日期：2023-01-22

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