Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury
Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury
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DOI：
10.1002/jor.24567
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发表时间：
2019-12-25
影响因子：
2.8
通讯作者：
Delco, Michelle L.
中科院分区：
文献类型：
--
作者：
Bartell, Lena R.;Fortier, Lisa A.;Delco, Michelle L.
创伤后骨关节炎（PTOA）涉及关节损伤后关节软骨的机械和生物学退化。PTOA是一个日益严重的卫生保健问题，由于缺乏有效的治疗方法，加上人口老龄化与高活动水平。最近，急性线粒体功能障碍和细胞呼吸改变与损伤后软骨退变有关。这一发现特别重要，因为最近开发的线粒体保护药物，包括SS肽，可以在其他组织急性损伤后保护线粒体结构和功能。然而，尚不清楚软骨损伤是否诱导线粒体的快速结构变化，软骨中线粒体功能障碍的程度取决于损伤的机制或这种功能障碍发展的时间范围。类似地，尚不清楚SS-肽治疗是否可以在软骨损伤后保留线粒体结构和功能。在这里，我们结合了快速相机弹性成像，纵向荧光测定和计算机视觉技术来跟踪数千个单个细胞的命运。我们的研究结果表明，影响诱导机械依赖性线粒体去极化损伤后几分钟内。电子显微镜显示，影响导致线粒体的结构迅速变化，这与线粒体功能降低有关，即分裂和嵴结构丧失。我们发现，SS-肽处理前的影响，保护线粒体结构，并保持线粒体功能的水平与未受影响的对照样品。总的来说，这项研究揭示了线粒体在介导软骨对创伤性损伤的超急性（几分钟内）反应中的重要作用，并证明了线粒体保护作为损伤诱导的软骨损伤的一种有前途的治疗策略。
Posttraumatic osteoarthritis (PTOA) involves the mechanical and biological deterioration of articular cartilage that occurs following joint injury. PTOA is a growing problem in health care due to the lack of effective therapies combined with an aging population with high activity levels. Recently, acute mitochondrial dysfunction and altered cellular respiration have been associated with cartilage degeneration after injury. This finding is particularly important because recently developed mitoprotective drugs, including SS peptides, can preserve mitochondrial structure and function after acute injury in other tissues. It is not known, however, if cartilage injury induces rapid structural changes in mitochondria, to what degree mitochondrial dysfunction in cartilage depends on the mechanics of injury or the time frame over which such dysfunction develops. Similarly, it is unknown if SS-peptide treatment can preserve mitochondrial structure and function after cartilage injury. Here, we combined fast camera elastography, longitudinal fluorescence assays, and computer vision techniques to track the fates of thousands of individual cells. Our results show that impact induces mechanically dependent mitochondrial depolarization within a few minutes after injury. Electron microscopy revealed that impact causes rapid structural changes in mitochondria that are related to reduced mitochondrial function, namely, fission and loss of cristae structure. We found that SS-peptide treatment prior to impact protects the mitochondrial structure and preserves mitochondrial function at levels comparable with that of unimpacted control samples. Overall, this study reveals the vital role of mitochondria in mediating cartilage's peracute (within minutes) response to traumatic injury and demonstrates mitoprotection as a promising therapeutic strategy for injury-induced cartilage damage.