The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

Abstract

Objective Mitochondrial dysfunction, oxidative stress and nucleus pulposus (NP) cell apoptosis are important contributors to the development and pathogenesis of intervertebral disc degeneration (IDD). Here, we comprehensively evaluated the effects of mitochondrial dynamics, mitophagic flux and Nrf2 signalling on the mitochondrial quality control, ROS production and NP cell survival in in vitro and ex vivo compression models of IDD and explored the effects of the mitochondria‐targeted anti‐oxidant MitoQ and its mechanism. Material and methods Human NP cells were exposed to mechanical compression to mimic pathological conditions. Results Compression promoted oxidative stress, mitochondrial dysfunction and NP cell apoptosis. Mechanistically, compression disrupted the mitochondrial fission/fusion balance, inducing fatal fission. Concomitantly, PINK1/Parkin‐mediated mitophagy was activated, whereas mitophagic flux was blocked. Nrf2 anti‐oxidant pathway was insufficiently activated. These caused the damaged mitochondria accumulation and persistent oxidative damage. Moreover, MitoQ restored the mitochondrial dynamics balance, alleviated the impairment of mitophagosome‐lysosome fusion and lysosomal function and enhanced the Nrf2 activity. Consequently, damaged mitochondria were eliminated, redox balance was improved, and cell survival increased. Additionally, MitoQ alleviated IDD in an ex vivo rat compression model. Conclusions These findings suggest that comodulation of mitochondrial dynamics, mitophagic flux and Nrf2 signalling alleviates sustained mitochondrial dysfunction and oxidative stress and represents a promising therapeutic strategy for IDD; furthermore, our results provide evidence that MitoQ might serve as an effective therapeutic agent for this disorder.

Neuroprotective Benefits of Exercise and MitoQ on Memory Function, Mitochondrial Dynamics, Oxidative Stress, and Neuroinflammation in D-Galactose-Induced Aging Rats

“…In the result of MitoQ, only the fusion protein Mfn1 and the fission protein Fis1 showed similar trends to TE, but the expression of the other proteins (Mfn2, Opa1, and Drp1) did not differ from that in the D-CON group. Previous studies using cell culture systems demonstrated that MitoQ improved oxidative stress-disrupted mitochondrial dynamics balance [ 38 ], as well as mitochondrial fission in a pharmacological model of Parkinson’s disease, inducing mitochondrial fragmentation [ 39 ], which is inconsistent with our findings from in vivo experiment due to methodological differences between in vitro and in vivo experiment. Therefore, further studies using our animal model are warranted on the use of MitoQ and mitochondrial dynamics, including considerations of dose and treatment duration.…”

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration

“…Idebenone as a CoQ derivative could complement respiration in fibroblasts, while mitochondria-targeted CoQ derivative (MitoQ or ubiquinol) demonstrated to be 800-fold more potent than idebenone to prevent cell death [ 121 ]. Studying on compression-induced NP cells, MitoQ restored mitochondrial function and prevented the loss of mitochondrial ∆Ψ m and mitochondria-mediated apoptosis [ 122 ]. MitoQ balanced mitochondrial dynamics via upregulation of mitochondrial fusion (Mfn) molecules Mfn1and Mfn2 as well as downregulation of fission molecule Drp1 to prevent cell death.…”

“…It also activated Nrf2 and its downstream molecules SOD 2 and NQO-1. Ex vivo study on rat tail disc has convincingly demonstrated the in vitro outcomes that MitoQ could re-organize AF collagen fibers, restored the size of NP tissue, and alleviated disc degeneration [ 122 ]. Overall, MitoQ would be a potent mitochondrial specific anti-oxidant that preserves mitochondrial homeostasis in NP cells.…”

“…PINK-1 silencing enhances NP cell senescence and ROS production either in a normal or oxidative stress-induced state, showing how mitophagy controls cell proliferation, aging, and perhaps IVD degeneration. Kang et al observed that the impaired mitophagy in the compression-induced human NP cells was attributed to the decreased activity of lysosomal enzymes [ 122 ]. Parkin knockdown promotes apoptosis and mitochondrial impairment in NP cells [ 135 ].…”

Long Noncoding RNA ANPODRT Overexpression Protects Nucleus Pulposus Cells from Oxidative Stress and Apoptosis by Activating Keap1‐Nrf2 Signaling

“…In a mouse model of IDD, degenerative changes in IVDs in Nrf2-knockout mice were more severe than those in wild-type mice [ 3 ]. We previously reported that the activation of the Nrf2 cascade is an effective strategy to protect human disc cells from oxidative damage and prevent IDD progression [ 14 , 15 ]. Therefore, Nrf2 signal plays an important role in IDD characterized by oxidative stress.…”