Clearing Damaged Mitochondria Cuts Lactate and Shields Spinal Discs From Degeneration

Low back pain is a leading cause of disability worldwide and is closely tied to intervertebral disc degeneration (IVDD). In degenerating discs, nucleus pulposus (NP) cells lose their hydrated, gel-like character and become fibrotic and senescent. Their extracellular matrix breaks down and chronic inflammation builds. Damaged mitochondria are a known driver. They release mitochondrial DNA and reactive oxygen species that activate cGAS–STING and NLRP3 inflammasome pyroptosis pathways. Mitophagy, the clearance of damaged mitochondria, is known to be protective. How it exerts that protection through cell metabolism has been unclear.

The authors hypothesized that mitophagy works partly by reprogramming lactate metabolism. Senescent NP cells with damaged mitochondria lean on glycolysis and accumulate lactate. Lactate can also act as a signal, since it is the substrate for histone lactylation, an epigenetic modification that can switch on inflammatory genes. The team therefore asked whether mitophagy could cut lactate, lower histone lactylation, and so dampen inflammation.

The available portion of the paper first establishes the disease model. NP tissue from spinal surgeries was graded on MRI by the Pfirrmann system, with grades I–II as nondegenerated and grade IV as degenerated. Primary NP cells from nondegenerated discs at passage 2 served as young controls. Serially passaged cells (passage 8) modeled in vitro aging, and passage-2 cells from degenerated discs modeled natural degeneration. Both aged and degenerated cells showed stronger senescence-associated β-galactosidase staining. RNA-seq (n = 3) showed enrichment of inflammation- and senescence-related genes, with 450 overlapping differentially expressed genes between the two comparisons. These genes were enriched in inflammatory pathways. Both cell types also showed mitochondrial membrane depolarization on JC-1 staining. Seahorse assays showed lower basal respiration, maximal respiration, ATP production, and spare respiratory capacity.

Per the abstract, the mitophagy activator TJ0113 drove metabolic reprogramming in senescent NP cells, with markedly lower lactate production. This reduced H3K18la and suppressed transcription of THBS1, a pro-inflammatory gene, blocking downstream inflammatory cascades. Genetic silencing of THBS1 and pharmacological inhibition of lactate generation were used to show that the lactate–H3K18la–THBS1 axis is essential for mitophagy's anti-inflammatory effect. A section heading indicates that TJ0113 was also tested in rat IVDD models. The text provided to me was cut off before those results.

The authors present this as the first evidence linking mitophagy to a metabolic–epigenetic regulatory axis in discs. It suggests that lactate production, histone lactylation, and THBS1 could be therapeutic targets for IVDD, beyond antioxidant or anti-inflammatory approaches.

Caveats: the evidence is preclinical, based on human-derived cell culture and animal models. The text I received was truncated, so quantitative effect sizes, the rat model data, and the detailed methods for the mechanistic experiments could not be assessed. TJ0113 is an experimental compound, and there is no human efficacy or safety data.