CircFUNDC1 interacts with CDK9 to promote mitophagy in nucleus pulposus cells under oxidative stress and ameliorates intervertebral disc degeneration.

Abstract

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, with limited effective treatments due to an incomplete understanding of disease mechanisms. In this study, we report that circFUNDC1, a nuclear circular RNA, is markedly downregulated in nucleus pulposus cells (NPCs) from patients with end-stage IVDD. CircFUNDC1 is derived from the gene encoding the FUN14 domain-containing 1 (FUNDC1) protein, which is essential for mitophagy and cell survival. Functional analyses reveal that circFUNDC1 plays a crucial role in maintaining extracellular matrix homeostasis by enhancing the expression of anabolic factors in NPCs. Additionally, we identified the transcriptional regulator cyclin-dependent kinase 9 (CDK9) as a novel binding partner for circFUNDC1. Binding with circFUNDC1 recruits CDK9 via complementary nucleotides to the FUNDC1 promoter to stimulate the production of full-length FUNDC1 mRNAs and proteins, forming a positive feedback loop. Overexpression of circFUNDC1 protects NPCs from oxidative stress by promoting mitophagy, reducing reactive oxygen species levels, and inhibiting cellular senescence. Moreover, circFUNDC1 overexpression delays the onset of IVDD in an ex-vivo culture model. This study is the first to demonstrate that circFUNDC1 is vital for protecting NPCs from oxidative stress, suggesting circFUNDC1 as a potential therapeutic target for IVDD.