Mitochondrial metabolism restoration via Tramiprosate suppresses mitochondrial ROS-driven foamy macrophage senescence post spinal cord injury.

BACKGROUND: Myelin debris (MD) engulfment-induced foamy macrophage formation is a core neuropathology following spinal cord injury (SCI). The accumulation of these foamy macrophages within the injured foci sustains neuroinflammation, impeding long-term neuroregeneration and functional recovery. However, the mechanism underlying macrophage deterioration post-foaming remains elusive. METHODS: MD-induced foamy macrophage and SCI model were used to investigated the role of Tramiprosate (TMP) in vivo and in vitro. Histological staining and functional assessments (gait analysis, Basso Mouse Scale, and motor evoked potentials) were conducted to evaluate the therapeutic effects of TMP on SCI. Quantitative PCR, western blotting, flow cytometry, immunofluorescence, seahorse assay and transmission electron microscopy were used to investigate the senescence and mitochondria function in foamy macrophages. RNA sequencing revealed TMP's role in restoring mitochondrial metabolism. And we injected AAV-shRNA to examine the potential molecular mechanism of TMP. RESULTS: The current study reveals that lipid droplet-laden foamy macrophages exhibit mitochondrial dysfunction and a senescent phenotype, characterized by increased secretion of matrix metalloproteinases and proinflammatory cytokines. Restoring mitochondrial metabolism via TMP-via upregulation of Shmt2-inhibits mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) leakage. This reduces oxidative damage to nuclear DNA and suppresses the cyclic GMP-AMP synthase (cGAS)-mediated inflammatory response, thereby eliminating senescence in foamy macrophages. CONCLUSIONS: Our work demonstrates that TMP is a potential therapeutic agent targeting mitochondrial dysfunction-induced macrophage senescence post SCI. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study investigates the mechanisms underlying macrophage senescence following SCI and identifies TMP as a potential therapeutic agent to mitigate this process. Importantly, TMP is a taurine analogue with established blood-brain barrier permeability and a favorable safety profile in prior clinical investigations for neurodegenerative diseases. These characteristics support its potential treatment strategy for SCI.