Activation of Sirt3 reprograms mitochondrial function to regenerate intervertebral disc degeneration.

BACKGROUND

Intervertebral disc degeneration is the principal pathological basis of low back pain. Currently, there are limited therapeutic strategies to regeneration intervertebral disc.

METHODS

Histological analyses were performed to assess phenotypic changes in the intervertebral discs of Sirt3 KO mice, and RNA-seq of intervertebral discs tissues was conducted. Differentially expressed genes were identified and further analyzed using GO, KEGG, and GSEA to elucidate biological processes and pathways regulated by Sirt3 during disc degeneration. A D-galactose-induced aging model was subsequently established, followed by treatment with the Sirt3 activator 2-APQC. Histology, RNA-seq, and immunofluorescence were used to validate key hub genes.

RESULTS

In study, we found the expression of SIRT3 is significantly negatively correlated with the degree of disc degeneration in human. Knockout of Sirt3 resulted in pronounced disc degeneration accompanied by increased expression of inflammatory mediators and senescence-associated factors. Transcriptomic analyses revealed that Sirt3 deficiency was closely associated with dysregulation of calcium signaling pathways and impaired ATP synthesis. Bioinformatics analyses identified Ckm and Atp2a1 as hub genes linking Sirt3 deficiency to calcium homeostasis disruption and ATP metabolic dysfunction. Importantly, the administration of Sirt3 activator 2-APQC significantly ameliorated intervertebral disc degeneration-associated pathological changes, evidenced by restored mitochondrial function, reduced inflammation and cellular senescence and rescued expression of hub genes Ckm and Atp2a1.

CONCLUSIONS

We unveiled the critical role of Sirt3 in maintaining mitochondrial homeostasis and mitigating intervertebral disc degeneration progression via regulating Ckm and Atp2a1. We provide a novel therapeutic strategy of activating of Sirt3 by 2-APQC to treat intervertebral disc degeneration.