Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

Abstract

Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.

Salvianolic Acid B Protects Intervertebral Discs from Oxidative Stress‐Induced Degeneration via Activation of the JAK2/STAT3 Signaling Pathway

“…Percutaneous needle puncture has been shown to be an effective method of induction of disc degeneration [ 32 ]. After acclimatization, animals were anesthetized by inhalation of 2% fluothane in oxygen/nitrous oxide.…”

Identification of Key Modules and Hub Genes of Annulus Fibrosus in Intervertebral Disc Degeneration

“…Some apoptosis, neural ingrowth, vascularization, and inflammation related terms and pathways were identified that were consistent with well-established molecular mechanisms of IDD (Kepler et al, 2013 ). The pathogenesis of IDD includes cellular oxidative stress, mitochondrial dysfunction and apoptosis (Kang et al, 2019 ). Endplate chondrocyte apoptosis is an important cause of the pathogenesis of cartilage endplate (CEP) degeneration, leading to the occurrence and development of intervertebral disc degeneration (IDD) (Wu et al, 2010 ; Li et al, 2014 ).…”

Cell Senescence: A Nonnegligible Cell State under Survival Stress in Pathology of Intervertebral Disc Degeneration

“…In addition, the ROS-induced autophagy inhibition is also proved to cause oxidative stress in many cell types [ 81 – 83 ]. And by enhancing and restoring impaired autophagy during IDD, Kang et al affirmed that excessive ROS production could be suppressed to protect the mitochondrial hemostasis and ameliorate NP cell senescence [ 84 ].…”