Optineurin-mediated mitophagy as a potential therapeutic target for intervertebral disc degeneration

Abstract

Low back pain is thought to be mainly caused by intervertebral disc degeneration (IVDD), and there is a lack of effective treatments. Cellular senescence and matrix degradation are important factors that cause disc degeneration. Mitochondrial dysfunction induced by oxidative stress is an important mechanism of cellular senescence and matrix degradation in the nucleus pulposus (NP), and mitophagy can effectively remove damaged mitochondria, restore mitochondrial homeostasis, and mitigate the damage caused by oxidative stress. Optineurin (OPTN) is a selective mitophagy receptor, and its role in intervertebral disc degeneration remains unclear. Here, we aimed to explore the effect of OPTN on H2O2-induced nucleus pulposus cell (NPCs) senescence and matrix degradation in a rat model of disc degeneration. Western blot analysis showed that OPTN expression was reduced in degenerative human and rat nucleus pulposus tissues and increased in H2O2-induced senescent NPCs. OPTN overexpression significantly inhibited H2O2-induced senescence and increased matrix-associated protein expression in NPCs, but OPTN knockdown showed the opposite effect. As previous reports have suggested that mitophagy significantly reduces mitochondrial damage and reactive oxygen species (ROS) caused by oxidative stress, and we used the mitophagy agonist CCCP, the mitophagy inhibitor cyclosporin A (CsA), and the mitochondrial ROS (mtROS) scavenger mitoTEMPO and confirmed that OPTN attenuated NPCs senescence and matrix degeneration caused by oxidative stress by promoting mitophagy to scavenge damaged mitochondria and excess reactive oxygen species, thereby slowing the progression of IVDD. In conclusion, our research suggests that OPTN is involved in IVDD and exerts beneficial effects against IVDD.

Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

“…Moreover, high glucose stress could increase ROS generation in AF cells in a dose‐and time‐dependent manner and induce cell senescence by activating the p16/Rb signalling axis, whereas inhibition of oxidative stress significantly alleviated cell senescence 206 . These results illustrated that oxidative stress could promote IVD cell senescence, while multiple studies confirmed that antioxidant treatment could effectively inhibit oxidative stress‐induced cell senescence to delay IDD progression 169,207,208 …”

“…206 These results illustrated that oxidative stress could promote IVD cell senescence, while multiple studies confirmed that antioxidant treatment could effectively inhibit oxidative stress-induced cell senescence to delay IDD progression. 169,207,208…”

Aging, Cellular Senescence, and Glaucoma

“…Mitophagy is reduced in aged cells, which leads to dysfunctional mitochondrial accumulation and ROS-induced senescence [111]. In fact, PINK1-PARKIN-mediated mitophagy plays a crucial regulatory role in attenuating cellular senescence in several diseases [112][113][114]. Although strong findings of reduced mitophagy were not obtained in D2 mice, several recent studies have demonstrated the protective effect of promoting PINK1/PARKIN-mediated mitophagy in RGCs in models of glaucoma (Table 1) [115][116][117].…”

Exosomes from umbilical cord mesenchymal stem cells ameliorate intervertebral disc degeneration via repairing mitochondrial dysfunction

“…However, excessive mitophagy causes elimination of mitochondria, leading to apoptosis [ 25 , 26 ]. The maintenance of mitophagy at a normal level is beneficial for protecting NPCs against oxidative stress and alleviating IVDD [ 27 , 28 ]. Accumulating evidence suggests that exosomes are also involved in intercellular mitochondrial communication.…”