SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis

Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates in the maintenance of mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 is involved in the impairment of mitochondria and development of IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression of the desuccinylase SIRT5 in rat nucleus pulposus (NP) tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated, whereas knockdown of Sirt5 aggravated, the apoptosis and dysfunction of NP cells under mechanical stress, consistent with the more severe IDD phenotype of Sirt5 KO mice than wild-type mice that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) results suggested that AIFM1 was a downstream target of SIRT5, which was verified by a Co-IP assay. We further demonstrated that reduced SIRT5 expression resulted in the increased succinylation of AIFM1, which in turn abolished the interaction between AIFM1 and CHCHD4 and thus led to the reduced electron transfer chain (ETC) complex subunits in NP cells. Reduced ETC complex subunits resulted in mitochondrial dysfunction and the subsequent occurrence of IDD under mechanical stress. Finally, we validated the efficacy of treatments targeting disrupted mitochondrial protein importation by upregulating SIRT5 expression or methylene blue (MB) administration in the compression-induced rat IDD model. In conclusion, our study provides new insights into the occurrence and development of IDD and offers promising therapeutic approaches for IDD. Investigation of a mitochondrial protein linked with intervertebral disc degeneration (IDD) provides possible therapeutic targets for lower back pain. Intervertebral discs act as shock absorbers in the spine, and excessive load over time can cause disc degeneration and pain. Liu Yang and Zhuojing Luo at Fourth Military Medical University in Xi’an, China, and co-workers analyzed the effect of excessive mechanical load on protein expression in IDD samples from human patients and rodent models. The sirtuin 5 (SIRT5) protein helps maintain healthy mitochondria, a key factor in protecting against disc degeneration. The team found that SIRT5 expression was reduced in IDD, which affected the activity of another protein and directly led to mitochondrial dysfunction and disc degeneration. Upregulating SIRT5 alleviated compression-induced IDD in rat models. Targeting the protein may prove useful for future treatments.