Volume 49 Number 3

Elamipretide coordinates OMA1/DELE1 signaling to modulate integrated stress response in cultured nucleus pulposus cells

Bo Lin, Shaoping Liu, Hongqiao Li, Yuanxue Tan^*

 
ABSTRACT:      Intervertebral disc degeneration (IDD) is a major cause of low back pain and disability. A central barrier is the unclear molecular link between mitochondrial dysfunction and the aberrant cellular stress responses that drive extracellular matrix breakdown, inflammation, and cell dysfunction in the nucleus pulposus (NP). Here, we identify the mitochondrial protease OMA1 as a previously unrecognized activator of the integrated stress response (ISR) in this context. Using LPS-induced inflammatory models, we show that OMA1 overactivation promotes the cleavage of its substrate DELE1, sustains eIF2? phosphorylation, and amplifies ATF4-dependent transcription, thereby exacerbating catabolic and pro-apoptotic programs. Conversely, the mitochondria-targeted peptide MTP-131 (or elamipretide) inactivates the OMA1/DELE1 pathway, suppresses ISR signaling, restores collagen and aggrecan synthesis, and reduces inflammatory cytokine release. These findings suggest the OMA1/DELE1 axis as a mechanistic hub that translates mitochondrial stress into disc pathology. It also reveals MTP-131 as a potential candidate for preserving mitochondrial homeostasis, offering a potential translational strategy for halting IDD progression.

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* Corresponding author, E-mail: 15826700478@163.com

Received 28 Apr 2026, Accepted 6 Jul 2026