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

Oxid Med Cell Longev. 2019 Dec 30:2019:7810320. doi: 10.1155/2019/7810320. eCollection 2019.

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.

MeSH terms

  • Adenylate Kinase / metabolism
  • Adolescent
  • Adult
  • Animals
  • Apoptosis / drug effects
  • Autophagosomes / drug effects
  • Autophagosomes / metabolism
  • Autophagy* / drug effects
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Cell Survival / drug effects
  • Cellular Senescence / drug effects
  • Curcumin / chemistry
  • Curcumin / pharmacology
  • Curcumin / therapeutic use
  • Disease Models, Animal
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Female
  • Humans
  • Intervertebral Disc Degeneration / drug therapy
  • Intervertebral Disc Degeneration / pathology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Male
  • Membrane Fusion / drug effects
  • Mitochondria / drug effects
  • Mitochondria / pathology*
  • Nucleus Pulposus / drug effects
  • Nucleus Pulposus / pathology
  • Oxidative Stress* / drug effects
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Young Adult
  • tert-Butylhydroperoxide

Substances

  • Intracellular Signaling Peptides and Proteins
  • tert-Butylhydroperoxide
  • Autophagy-Related Protein-1 Homolog
  • TOR Serine-Threonine Kinases
  • ULK1 protein, human
  • Adenylate Kinase
  • Curcumin