Introduction

Low back pain (LBP) is an extremely prevalent musculoskeletal disorder worldwide, and almost everyone suffers an acute or chronic episode of LBP during their lifetime1. According to the statistical analysis of the Global Burden of Disease Study 2017, LBP was consistently the leading contributor to the increase in years lived with a disability2. Intervertebral disc degeneration (IDD), which results in progressive spinal deformity, stenosis, and the inflammatory response, has been identified as a well-known contributor to LBP3,4. Nevertheless, current clinical therapeutic strategies, known as conservative treatment and surgical intervention, aimed at alleviating symptoms rather than targeting IDD directly1. Further clarifying the molecular mechanism of IDD will provide a new approach for precise intervention strategies for LBP.

Normal intervertebral discs consist of gelatinous nucleus pulposus (NP) as the central structure, surrounded by lamellar annulus fibrosus (AF) and sandwiched by superior and inferior cartilaginous endplates (CEPs)5. The gelatinous NP tissue is critical for the physiological function of intervertebral discs to absorb and disperse mechanical loadings during spinal motion, such as flexion, extension, bending, and rotation5. Currently, NP cells are identified as the main cell group that undergoes anabolic and catabolic metabolism and maintains extracellular matrix homeostasis. Mounting evidence has demonstrated that the loss of function of NP cells through senescence, apoptosis, necroptosis, inflammatory response, or phenotypic change plays important roles in inducing the dehydration of NP tissue and promoting IDD progression6,7,8.

Although the intervertebral disc has been identified as the largest avascular organ and found to generate energy through anaerobic glycolysis9,10, a critical role for mitochondria in promoting metabolic adaptation has been suggested11,12. In addition to material and energy metabolism, mitochondria also participate in regulating the function of second messengers, such as reactive oxygen species (ROS) and calcium, and the activation of various signaling pathways, which play important roles in regulating cellular function and determining cell fates13. In IDD progression, structural and functional abnormalities in mitochondria have been observed in NP cells6,14,15. Mitochondrial quality control (MQC), involving molecular, organellar, and cellular level mechanisms, is considered a critical surveillance and protective system for limiting mitochondrial damage and ensuring mitochondrial integrity16 (Fig. 1). Dysfunctional MQC strategies and aggravated mitochondrial damage are considered major contributing factors in promoting NP cell function loss6,17.

Fig. 1: The molecular, organellar, and cellular levels of MQC strategies that maintain mitochondrial homeostasis.
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With increasing stress magnitude, multilevel and well-orchestrated MQC strategies are implemented. Mitochondrial proteostasis is monitored by UPRmt activity and executed by ATF5, which mainly promotes the expression of mitochondrial chaperones and proteases that conduct the refolding or proteolysis of misfolded and damaged proteins. Under primary and secondary oxidative stress, mitochondrial antioxidant members (SOD2, Gpx1/4, Prx3, Trx2, TrxR2) eliminate superoxide radicals and maintain redox homeostasis. Further damage can induce the selective separation of healthy and injured mitochondria by Drp1-dependent fission. The remaining intact daughter mitochondria are replenished by mitochondrial biogenesis involving mitochondrial transcription factor-mediated (TFAM) mtDNA and nuclear transcription factor-mediated (PGC-1, NRFs, ERRs, PPARs) DNA expression and integrated by OPA1/MFN-dependent fusion, while the disrupted daughter mitochondria are swallowed and degraded by mitophagy, which depends on ubiquitinated mitochondrial substrates (S) in the PINK1/Parkin ubiquitin pathway or other mitophagy receptors (BNIP3/NIX, FUNDC1, or cardiolipin). Finally, irreversible damage to mitochondria induces devastating effects on cellular bioactivities and results in apoptosis. Healthy MQC strategies succeeded in maintaining good intervertebral disc morphology (A1) and mitochondrial homeostasis through mitochondrial elongation and integral structure (B1), high mitochondrial membrane potential (C1), low ROS levels (D1), and fine-tuned NP cell status (E1). Defective MQC strategies aggravate intervertebral disc morphologic disruption (A2) and fail to maintain mitochondrial homeostasis and exhibit mitochondrial fragmentation (B2), low mitochondrial membrane potential (C2), high ROS levels (D2), and poor NP cell status (E2). Interpretively, intervertebral disc morphology was defined on the basis of T2-weighted magnetic resonance imaging (A1/A2), mitochondrial structure as assessed with MitoTracker Red CMXRos staining (B1/B2), mitochondrial membrane potential as determined by JC-1 assay (C1/C2), ROS levels as measured using 2′,7′-dichlorofluorescin diacetate staining (D1/D2), and NP cell status as assessed using senescence-associated β-galactosidase staining (E1/E2).

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In this review, we summarize defective MQC strategies linked to mitochondrial dysfunction that contribute greatly to NP cell function loss and IDD progression. Relevant molecular strategies with clinical translational potential that might be developed for the prevention and treatment of IDD progression are also discussed.

Mitochondrial dysfunction and IDD pathogenesis

Although in some studies, few mitochondria were detected in adult NP tissue specimens14,18, well-developed mitochondria exist in NP cells, especially in fetal NP cells19,20,21. Multiple studies have confirmed that the etiological factors in IDD pathogenesis are involved in endogenous genetic predisposition and exogenous stressors, such as decreased nutrient transport, mechanical overloading, diabetes, smoking, infection, and aging4. Interestingly, all these etiological mechanisms are associated with mitochondrial damage, which has been proposed to underlie the pathophysiology of NP cell function loss and IDD progression.

First, the early degenerative process of notochord-like NP cells due to phenotypic changes or cell death was partially attributed to loading, avascularity, and the hypoxic and hyperglycemic microenvironment, in which increased mitochondrial fission, fragmentation, mitophagy and mitochondrial damage play adaptive and aggravating roles22,23,24,25,26. Due to the origination of the notochord, NP cells present notochordal markers, also called notochord-like NP cells, and are regarded as indicative of the initial cell phenotype in NP tissue27,28,29,30. With disc maturation, the supplies of nutrients and oxygen were diminished, especially in the central NP tissue, which induced the loss of the notochord-like phenotype in NP cells, partially due to its more active metabolism and greater susceptibility to nutrient deprivation, compared with chondrocyte-like NP cells24. Mitochondria loss may be an adaptive process. Similarly, the absence of a master regulator adapting the cells to hypoxia, namely, hypoxia-inducible factor (HIF)-1α, may also promote cell death and NP dysplasia, which is accompanied by disordered mitochondrial oxidative metabolism and mitophagy31,32,33. Loading stress can also promote the transition of notochord-like NP cells to chondrocyte-like NP cells or induce the apoptotic death of notochord-like NP cells, in which a mitochondrial pathway plays a partial role23,26,34. In diabetes-associated diseases, hyperglycemia can disrupt mitochondrial function and induce notochordal cell death25,35. Recently, targeting notochordal cells as regenerative strategies of NP tissue has been recommended, and this strategy includes notochordal cell coculture, notochordal cell-conditioned medium, and notochordal cell matrix36,37,38,39,40,41. Whether the function of notochord-like NP cells can be rescued by modeling mitochondrial function needs to be determined through more investigation.

Second, NP cell function loss occurs in the IDD progression stage due to cell senescence, death, inflammatory responses, and imbalances in anabolic and catabolic metabolism, which are also closely associated with mitochondrial damage8,42,43,44,45,46,47,48,49. In addition to the deficiency of energy generation, damaged mitochondria negatively affect cellular function by releasing various deleterious molecules. Studies have confirmed that many risk factors associated with IDD progression, including mechanical overloading, inflammation, nutrition deprivation, and the accumulation of advanced glycation end products (AGEs) or progerin, can cause excessive ROS production, calcium disorders, and the leakage of pro-death factors such as cytochrome C and apoptosis-inducing factor6,8,17,47,48,50,51. These hazardous molecules can act alone or jointly, composing a complex network in the mechanism of IDD pathogenesis. Although various ROS scavengers, antioxidants and calcium chelators can inhibit NP cell senescence or death in experiments conducted in vitro and alleviate IDD progression in experimental animal models52,53,54,55, none of these agents have been translated into clinical application with satisfactory therapeutic efficiency in patients with IDD or IDD-related complications. These studies implied that the release of harmful molecules was merely a consequence of mitochondrial disruption, and targeting these damaging molecules may require salvage therapies, not fundamental strategies. In contrast, a pool of healthy mitochondria maintained by an elaborate MQC system seems to lay a better foundation for controlling the production of mitochondrial-derived danger molecules. Presumably, this control can be achieved by elucidating and manipulating the critical MQC strategies in specific pathogeneses to achieve efficient coordination of mitochondrial metabolism, incidental mitochondrial damage, and mitochondrial regeneration. Some studies have attempted to investigate precise MQC strategies and elucidate the corresponding therapeutic targets (Table 1).

Table 1 Defective MQC strategies are attributed to IDD progression induced by various risk factors.
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The MQC system in IDD pathogenesis

Mitochondrial proteostasis

Generally, the unfolded protein response (UPR) is referred to as a protective signaling pathway that dissolves accumulated damaged and/or unfolded/misfolded proteins and reestablishes cellular proteostasis56,57. In mitochondria, a diverse number of stressors that impair mitochondrial function can induce the mitochondrial unfolded protein response (UPRmt), mediating adaptive transcriptional activity and promoting the recovery of the mitochondrial network58,59. First, the increased expression of mitochondria-localized molecular chaperones induced by UPRmt activity, such as Hsp70 and Hsp60, not only can facilitate the correct folding of newly synthesized proteins but can also unfold and disaggregate misfolded proteins60,61. Second, the UPRmt can also enhance the expression of a significant number of mitochondrial proteases, such as LONP1 and CLPP, which are important for protein maintenance and elimination of oxidized and damaged proteins62. In addition, the UPRmt can promote the expression of nuclear-encoded detoxification enzymes and mitochondrial protein-imported components63,64.

In one model of collagen microencapsulation, the stress response of NP cells to compression loading was examined65. It was found that longer loading durations significantly upregulated the Hsp70 level and had little influence on the apoptosis ratio of the NP cells, which indicated a protective effect following mechanical stress65. In addition, this research team also used adult bovine caudal discs to construct an organ culture model and found that Hsp70 expression appeared to be upregulated immediately after loading and was decreased upon resting following a repeated loading cycle in NP cells but not in AF cells66. In addition, a hypoxic or hypertonic microenvironment showed dramatic effects on mitochondrial function in NP cells21,33,53, in which the levels and function of the mitochondrial chaperone Hsp70 presented a corresponding response67,68. Shilpa et al.67 found that tonicity enhancer-binding protein (TonEBP) and HIFs are involved in some interaction that leads to the regulation of Hsp70 levels, while Hsp70 function also negatively regulates HIF-1α protein stability and transcriptional activity. Studying the hyperosmotic microenvironment, Tsai et al68 confirmed an adaptive response of NP cells to hyperosmotic stress depending on the activity of the important osmoregulator TonEBP, and its target gene, Hsp70, contributed greatly to this response. Thus, the mitochondrial chaperone Hsp70 plays critical role in regulating mitochondrial function and adaptive responses of NP cells to various stresses. The complex function of UPRmt involves many upstream regulators and downstream mediators. Future studies need to fully characterize the UPRmt process in the progression of IDD pathogenesis and NP cell function loss.

Mitochondrial antioxidant system

Along with mitochondrial respiration and metabolism, ROS are commonly generated, such as superoxide anion and hydrogen peroxide (H2O2)69,70. The antioxidant system in mitochondria largely contributes to monitoring and controlling cellular ROS levels. Multiple antioxidant enzymes participate in the construction of the mitochondrial antioxidant system, including superoxide dismutases (SODs), glutathione peroxidases (Gpxs), peroxiredoxins (Prxs), and some enzymes that exhibit redundant actions70,71,72. SODs can dismutate superoxide anions to H2O2, and SOD2 is mainly located in mitochondria71. Subsequently, Gpxs/Prxs can catalyze H2O2 to H2O, mainly through Gpx1/4, Prx3, Trx2, and TrxR2, in mitochondria72. A healthy antioxidant system is crucial in determining whether ROS are playing “friends” or “foes” roles, which partially depends on their concentration, location, and functional context73,74. Appropriate or low ROS levels contribute to multiple essential biochemical signaling processes ranging from cell metabolism to microorganism defense. Excessive generation and/or inadequate elimination of ROS results in oxidative damage to molecules and oxidative stress, which has been implicated in various pathogeneses and, in the case of cancer, in roles that protect tumors from elimination.

In IDD pathogenesis, it has been demonstrated that various risk factors, such as mechanical overloading, AGE accumulation, nutrient deprivation, and inflammatory cytokines, can promote IDD events by inducing oxidative stress6,42,52,75,76. Under compression conditions, NP cells showed significantly decreased protein levels of SOD2, which could be rescued by MitoQ treatment, and they showed antioxidant function52. It was found that the reduction in SOD and Gpx activity levels was involved in TNF-α-induced oxidative stress in human NP cells and that the rescue of SOD and Gpx activity levels by administration of ginsenoside Rg3 reversed this degenerative process77. In ovariectomized animal models, IDD progression was associated with disrupted redox homeostasis involving the functional loss of SOD, Gpx, and GSSG/GSH balance78. Estrogen supplementation can enhance antioxidant capacity and correct redox imbalance stress78. In addition, the partial or whole functional deficiency of mitochondrial antioxidant enzymes is also critical in many other IDD processes induced by hyperosmolarity, mechanical overloading, AGE accumulation, or lipopolysaccharide6,49,79,80. The effects of biologically active components used to treat IDD have greatly improved in recent years. It has been confirmed that honokiol, nicotinamide mononucleotide, melatonin, plumbagin, and pilose antler peptide can efficiently enhance the catalytic activity of SOD and/or Gpx, which contributes substantially to resistance to oxidative stress and IDD progression6,81,82,83,84. More investigation and clarification targeting the mitochondrial antioxidant system will provide clearer strategies for IDD intervention.

Mitochondrial dynamics

Dynamic mitochondria are identified by high fusion and fission activities, ensuring their efficient response to changing requirements for energy production, calcium homeostasis, lipid biogenesis, fatty acid synthesis, and responses to stress conditions85. In quiescent cells, increased mitochondrial fission converts functionally mature mitochondrial networks into immature states that are applicable for conditions of low metabolic demand and reduced oxidate exposure86. Under stress or proliferative conditions, however, activated mitochondrial fusion activity can maximize the oxidative capacity for energy demand and increase the degree of cross-complementation for attenuating defective mitochondria, enhancing their response capacity87,88,89. A healthy balance of dynamic mitochondrial activity is well regulated by large dynamin-related guanosine triphosphatases (GTPases)90. Long-form optic atrophy1 (L-Opa1) and mitofusin1/2 (Mfn1/2) are correspondingly critical for inner and outer mitochondrial membrane fusion, and dynamin-like protein (Drp1) and short-form Opa1 (S-Opa1) are correspondingly critical for outer and inner mitochondrial membrane fission. In addition, other factors have also been found to assemble the fusion and fission machinery, such as mitoPLD, FIS1, MFF, MiD49, and MTP1890. Both innate mutations and acquired stressors that disturb the healthy fusion and fission machinery can induce pathological mitochondrial dynamics91,92,93.

It has been proven that disrupted mitochondrial dynamics are also closely related to mitochondrial dysfunction and oxidative stress in the IDD process. Xu et al found that progerin accumulation in human NP tissues was associated with IDD progression, and further study confirmed that progerin stimulation can shift mitochondrial dynamics toward fission events by decreasing the levels of mitochondrial fusion factors Opa1 and Mfn1/2 and increasing the levels of the mitochondrial fission factor Drp117. By rescuing the balance of mitochondrial dynamics, sulforaphane can significantly attenuate progerin-induced mitochondrial dysfunction and NP cell senescence17. Using a mechanical overloading model of IDD, Kang et al observed that the migration of Drp1 from the cytoplasm to mitochondria was significantly enhanced. Similarly, the total protein levels of Drp1, Mff, and Fis1 were significantly upregulated and those of Opa1 and Mfn1/2 were downregulated by mechanical overloading, which largely contributed to NP cell damage and was ameliorated by MitoQ intervention52. Similarly, hydrogen sulfide treatment can also decrease the mitochondrial membrane location of Drp1 and mitochondrial dysfunction induced by proinflammatory factors50. These results may suggest that rebalancing healthy mitochondrial fusion/fission dynamics is critical for IDD intervention.

Mitophagy

In contrast to bulk autophagy, in which cellular components are recycled to meet nutrient demand, selective autophagy functions to clear unwanted and damaged substances94. Autophagy that is specific to mitochondria is referred to as mitophagy, which is crucial for the elimination of damaged or superfluous mitochondria95,96. The principal mechanisms of selective autophagy rely on the use of specialized cargo-binding adaptor proteins, also called selective autophagy receptors97. Members of the PARK family, PARK2 and PARK6, which encode the E3-Ub ligase PARKIN and the mitochondrial-targeted kinase PINK1, respectively, were shown to be key mediators of mitophagy and mitochondrial surveillance. The accumulation of PINK1 on the mitochondrial surface is the first step to sensing mitochondrial stress. Depolarization of the mitochondrial membrane, decreasing its potential, prevents the import of PINK1 through the mitochondrial membrane and secondary proteolytic cleavage, which leads to the effective accumulation of full-length PINK1 and its activating autophosphorylation. Activated PINK1 can phosphorylate ubiquitin and elicit PARKIN recruitment to the mitochondrial surface. Ultimately, the PINK1-PARKIN pathway results in ubiquitinated mitochondrial substrates (S), autophagy receptor recruitment, and clearance of damaged mitochondria98,99,100. In addition to the PINK1-PARKIN pathway, several selective mitochondrial autophagy receptors have been identified: BNIP3/NIX, FUNDC1, NLRX1, and PHB2100,101. Some lipid autophagy receptors have also been identified102,103. Cardiolipin, a lipid unique to mitochondria, has recently been reported to mediate mitophagy103.

It has been observed that the mitophagy process in NP cells can be induced by mechanical loading, TNF-α expression, and exogenous hydroperoxide treatment, which is beneficial for alleviating NP cell senescence, preventing cell death, and correcting imbalances in anabolic/catabolic metabolism52,104,105. Based on this, targeting the PINK1-PARKIN pathway by natural extracts, such as salidroside and melatonin, may promote effective mitophagy and its beneficial effects104,106. Noncoding RNAs targeting molecules upstream of the PINK1-PARKIN pathway also have been shown to exert a positive effect on mitophagy107. In addition, other mitophagy receptors, such as BNIP3, were found to mediate the selection and elimination of damaged mitochondria and promote the resistance of NP cells to oxidative stress108. The outcome of mitophagy as beneficial or detrimental in disease progression and/or intervention is a cellular factor- and context-dependent109,110. Under strong oxidative conditions, excessive mitophagy is induced in NP cells, which contributes greatly to the promotion of apoptotic cell death32. This study also identified the critical role of HIF-1α/NDUFA4 L2 in repressing excessive mitophagy and alleviating NP cell apoptosis32. Thus, more clarification of mitophagy mechanisms in IDD progression may provide precise therapeutic targets for driving the beneficial effect of mitophagy in IDD intervention.

Mitochondrial biogenesis

Mitochondrial biogenesis is an important process that promotes the synthesis of new mitochondria through expansion and division of pre‐existing mitochondria, which reach and maintain mitochondrial homeostasis by obtaining a balance between mitochondrial fission and fusion and realizing mitochondrial turnover through mitophagy111. As semiautonomous organelles, mitochondrial proteins not only transcribe and translate nuclear and mitochondrial genomes but also synchronize and coordinate their expression112. Multiple transcription factors and coactivators have been shown to orchestrate genome expression during mitochondrial biogenesis113. Nuclear respiratory factors (NRF1/2) were the first nuclear transcription factors found to be involved in the transcription of several mitochondrial genes that mainly encode subunits of mitochondrial respiratory chain complexes114. Members of the nuclear receptor (NR) superfamily, mainly peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs), are also important for controlling the transcription of nuclear genes encoding mitochondrial substrates involved in FAO, the TCA cycle, and ETC/OXPHOS115. In addition, peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) coactivators build regulatory circuitry and serve as central components to control the transcriptional activities of NRF and NR family proteins115. PGC-1/NRF-1 coactivation is also critical for the expression of TFAM, a transcription factor of the mitochondrial genome encoding 13 components of OXPHOS system complexes116. Hua et al.117 observed that icariin can significantly rescue mitochondrial function in human NP cells by activating the NRF1/2 and TFAM pathways and promoting mitochondrial biogenesis. Other studies have also observed the functions of PGC-1 and NRFs in protecting mitochondria against damage in NP cells6,52,108, but whether mitochondrial biogenesis is involved in this protection remains to be elucidated.

Cellular elimination of mitochondria

In the case of sustained mitochondrial stress and irreversible mitochondrial damage, the cellular quality control mechanisms that rely on apoptosis and the turnover of entire cells are engaged to ensure the homeostasis of the organism. Otherwise, damaged mitochondria would be transferred to neighboring cells, and malfunctioning cells can accumulate and lead to tumor development and other pathological conditions118,119. Indeed, extensive mitochondrial damage promotes prolonged mitochondrial outer membrane permeabilization (MOMP), which can contribute to the release of proapoptotic molecules such as cytochrome c, Diablo, HtrA2, and AIF from the mitochondrial intermembrane space into the cytosol, resulting in caspase activation and apoptosis120. The well-characterized mechanism that invokes MOMP is dependent on Bax-Bak oligomerization and translocation to the mitochondrial outer membrane where pores or channels are formed to generate MOMP. In addition, this process is also affected by pro-survival members of the Bcl-2 family (Bcl-2, Bcl-xL), which either bind to Bax-Bak and prevent their oligomerization or are “neutralized” by the restraint of BH3-only proteins (Bid and Bad); the outcome of Bcl-2 family proteins dictates whether a cell survives or undergoes apoptosis121. Another model of channel formation is mediated by voltage-dependent anion channel (VDAC), the most abundant protein of the mitochondrial outer membrane109. Furthermore, crosstalk between VDAC and members of the Bcl-2 (homology) family have also detected and found to function together to mediate cytochrome c release and cell apoptosis. Thus, damaged mitochondrial substrates promote cell apoptosis that eliminates whole cell contents, including damaged mitochondria, at the cellular level of MQC. In the progression of IDD, mitochondria-derived signals have been confirmed to promote Bax-Bak oligomerization and further induce MOMP and NP cell apoptosis in various risk factor-induced degenerative models6,122. However, recent studies have mostly focused on the effect of damaged mitochondria on NP cell apoptosis, but not the other forms of cell death. Recently, multiple studies demonstrated various cell death models in the IDD process, including ferroptosis123, pyroptosis124, and necroptosis125, all of which are closely associated with mitochondrial damage. Cells commit suicide at the appropriate time as part of the natural cell turnover process that is essential to optimal tissue functioning, while more investigation and clarification between mitochondria-associated cell death and the cellular level of MQC are needed.

Concluding remarks and future perspectives

MQC is tightly associated with adaptive changes in mitochondrial metabolism and the timely elimination of mitochondrial damage. Multiple levels of MQC action and surveillance strategies were involved in the mitochondrial adaptive response and defective mitochondrial elimination for the maintenance of mitochondrial homeostasis. Indeed, well-orchestrated coordination and balance within MQC functional strategies efficiently maintain healthy mitochondrial metabolism (Fig. 2). For instance, eliminating damaged mitochondrial proteins by proteases or mitophagy and renewing components by adding protein and lipids through biogenesis or UPRmt enables the monitoring and regulation of mitochondrial protein quality112. The mitochondrial network can be fragmented and segregated by fission, which requires synergistic fusion of healthy fragments and selective mitophagy to eliminate damaged mitochondrial fragments126. In addition, mitophagy must be coordinated with new mitochondrial production through fusion/fission and biogenesis to control mitochondrial mass127,128.

Fig. 2: The well-orchestrated coordination and balance among MQC strategies are essential for protecting against mitochondrial dysfunction.
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Mitochondrial proteostasis, antioxidants, biogenesis, and fusion work to maintain the healthy status of existing mitochondria or to generate new mitochondria. In parallel, mitochondrial fission, mitophagy, and apoptotic elimination lead to the separation and removal of old and damaged mitochondria. Either incompatible repair or elimination activities can promote mitochondrial dysfunction.

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Abnormal MQC function was consistently observed in the IDD process. Each mechanism of MQC, including UPRmt, mitochondrial antioxidants, mitochondrial dynamics, mitophagy, and biogenesis, functions in regulating NP cell death, senescence, the inflammatory response, and anabolic and catabolic metabolism. Targeting one or several mechanisms of MQC has shown therapeutic potential for IDD intervention. However, the relative contribution of each mechanism to IDD progression remains largely unknown. In addition, crosstalk between different mechanisms also exists, and it is essential to identify the molecular underpinnings that regulate and coordinate these processes to achieve optimal MQC, thereby reducing NP cell function loss and IDD progression. Further investigation aiming to understand the molecular mechanisms and develop therapeutic strategies individually or in combination that target efficient MQC processes is expected.