Mitochondrial quality control in intervertebral disc degeneration

Abstract

Intervertebral disc degeneration (IDD) is a common and early-onset pathogenesis in the human lifespan that can increase the risk of low back pain. More clarification of the molecular mechanisms associated with the onset and progression of IDD is likely to help establish novel preventive and therapeutic strategies. Recently, mitochondria have been increasingly recognized as participants in regulating glycolytic metabolism, which has historically been regarded as the main metabolic pathway in intervertebral discs due to their avascular properties. Indeed, mitochondrial structural and functional disruption has been observed in degenerated nucleus pulposus (NP) cells and intervertebral discs. Multilevel and well-orchestrated strategies, namely, mitochondrial quality control (MQC), are involved in the maintenance of mitochondrial integrity, mitochondrial proteostasis, the mitochondrial antioxidant system, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Here, we address the key evidence and current knowledge of the role of mitochondrial function in the IDD process and consider how MQC strategies contribute to the protective and detrimental properties of mitochondria in NP cell function. The relevant potential therapeutic treatments targeting MQC for IDD intervention are also summarized. Further clarification of the functional and synergistic mechanisms among MQC mechanisms may provide useful clues for use in developing novel IDD treatments.

Fig. 1. The molecular, organellar, and cellular levels of MQC strategies that maintain mitochondrial homeostasis.

With increasing stress magnitude, multilevel and well-orchestrated MQC strategies are implemented. Mitochondrial proteostasis is monitored by UPR^mt 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).

Fig. 2. The well-orchestrated coordination and balance among MQC strategies are essential for protecting against mitochondrial dysfunction.

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.