Involvement of DJ-1 in the pathogenesis of intervertebral disc degeneration via hexokinase 2-mediated mitophagy

• Published in: Experimental & molecular medicine Vol. 56; no. 3; pp. 747 - 759
• Main Authors: Lin, Jialiang, Wang, Longjie, Wu, Yuhao, Xiang, Qian, Zhao, Yongzhao, Zheng, Xuanqi, Jiang, Shuai, Sun, Zhuoran, Fan, Dongwei, Li, Weishi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2024; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/2; 13/89; 14/28; 14/34; 14/63; 38/1; 38/109; 59/57; 631/80/82/23; 692/420; 82/80; AKT protein; Apoptosis; Artificial intelligence; Biomedical and Life Sciences; Biomedicine; Degeneration; Degenerative disc disease; Hexokinase; Intervertebral discs; Localization; Low back pain; Medical Biochemistry; Mitochondria; Mitophagy; Molecular Medicine; Molecular modelling; Nucleus pulposus; Oxidative stress; PARK7 protein; Parkin protein; Pathogenesis; Public health; Spine; Stem Cells; Therapeutic targets; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01196-0

Intervertebral disc degeneration (IDD) is an important pathological basis for degenerative spinal diseases and is involved in mitophagy dysfunction. However, the molecular mechanisms underlying mitophagy regulation in IDD remain unclear. This study aimed to clarify the role of DJ-1 in regulating mitophagy during IDD pathogenesis. Here, we showed that the mitochondrial localization of DJ-1 in nucleus pulposus cells (NPCs) first increased and then decreased in response to oxidative stress. Subsequently, loss- and gain-of-function experiments revealed that overexpression of DJ-1 in NPCs inhibited oxidative stress-induced mitochondrial dysfunction and mitochondria-dependent apoptosis, whereas knockdown of DJ-1 had the opposite effect. Mechanistically, mitochondrial translocation of DJ-1 promoted the recruitment of hexokinase 2 (HK2) to damaged mitochondria by activating Akt and subsequently Parkin-dependent mitophagy to inhibit oxidative stress-induced apoptosis in NPCs. However, silencing Parkin, reducing mitochondrial recruitment of HK2, or inhibiting Akt activation suppressed DJ-1-mediated mitophagy. Furthermore, overexpression of DJ-1 ameliorated IDD in rats through HK2-mediated mitophagy. Taken together, these findings indicate that DJ-1 promotes HK2-mediated mitophagy under oxidative stress conditions to inhibit mitochondria-dependent apoptosis in NPCs and could be a therapeutic target for IDD.
Unlocking IDD therapy: DJ-1’s role in mitophagy regulation revealed
Low back pain, often due to intervertebral disc degeneration (IDD - a condition where the disks in the spine break down), is a common global health problem. Current treatments mainly aim at pain relief and surgery, but effective methods to slow or reverse the degeneration are lacking. This research, led by Jialiang Lin and team, investigates the role of a protein, DJ-1, in protecting nucleus pulposus cells. They conducted experiments with NPCs and discovered that DJ-1 can shield these cells from damage caused by oxidative stress by promoting mitophagy (a process that controls the number and quality of mitochondria - the cell’s energy producers). The study also found that another protein, hexokinase 2 (HK2), helps DJ-1 in this protective role. The results suggest that DJ-1 could be a potential treatment target for IDD.
This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.