Mitoprotective therapy prevents rapid, strain‐dependent mitochondrial dysfunction after articular cartilage injury

Abstract

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.

Cartilage articulation exacerbates chondrocyte damage and death after impact injury

“…16,17 While mitochondrial repolarization is possible, prolonged depolarization past an unknown threshold of time leads to mitochondrial damage and depending on the severity can induce cell death by apoptosis or necrosis if the damage is extensive. 18,19 While there are promising new chemical interventions to halt the progression of mitochondrial and other biochemical processes, 20,21 the current standard of care is to prescribe rehabilitation therapy to improve supporting musculature strength, joint functionality, and decrease pain. [22][23][24] It is unknown, however, if movement soon after joint injury is beneficial or detrimental to long-term outcome and the development of PTOA.…”

Mitochondria in Injury, Inflammation and Disease of Articular Skeletal Joints

“…These studies once again show that mitochondrial function is critical for maintenance of cellular energy production via the gradient created in the ETC in joint tissues. Pathogenic unfolding of membrane cristae and loss of membrane polarisation are characteristic of diseases in many tissues, but it is interesting to note that the same has recently been shown to be true in OA (76). These studies also support the potential application of antioxidants and targeting chondrocyte mitochondrial metabolism after injury to mediate PTOA and promote healthy cartilage (75).…”

Synovial Fluid Mitochondrial DNA Concentration Reflects the Degree of Cartilage Damage After Naturally Occurring Articular Injury

“…Mechanotransduction is known to influence chondrocyte function. Specifically, studies have demonstrated strain-dependent mitochondrial dysfunction (41, 59) and ROS release (60) in chondrocytes. As several of the proposed mechanisms for active mtDNA release occur in response to mitochondrial dysfunction and increased ROS production (26, 29, 30) , mechanotransduction may represent an important link between mechanical injury and active mtDNA release.…”