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Updated: May 12, 2026
Assessing Mitochondrial Function in Sciatic Nerve by High-Resolution Respirometry
Published on: May 5, 2022
Mitochondrial metabolism restoration via Tramiprosate suppresses mitochondrial ROS-driven foamy macrophage senescence
Chaoqin Wu1, Qihao Fu2,3, Jianlan Liu1
1Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
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.
Insights
Tramiprosate (TMP) reverses macrophage senescence after spinal cord injury (SCI) by restoring mitochondrial function. This finding offers a potential therapeutic strategy for improving neuroregeneration and functional recovery following SCI.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Foamy macrophage formation from myelin debris engulfment is a key pathology in spinal cord injury (SCI), driving neuroinflammation and hindering recovery.
- The mechanisms behind macrophage dysfunction after becoming foamy remain unclear, representing a critical knowledge gap in SCI research.
Purpose of the Study:
- To investigate the role of Tramiprosate (TMP) in mitigating macrophage senescence and dysfunction following SCI.
- To elucidate the underlying mechanisms by which TMP impacts foamy macrophage phenotype and mitochondrial function.
Main Methods:
- Utilized an SCI model and foamy macrophages in vitro to assess TMP's therapeutic effects using histological, functional, molecular, and cellular assays.
- Employed techniques including qPCR, Western blotting, flow cytometry, Seahorse assay, and transmission electron microscopy to analyze senescence and mitochondrial function.
- Conducted RNA sequencing and AAV-shRNA injections to explore TMP's molecular mechanisms.
Main Results:
- Foamy macrophages exhibit mitochondrial dysfunction and senescence, secreting pro-inflammatory factors.
- TMP treatment restored mitochondrial metabolism by upregulating Shmt2, reducing mitochondrial reactive oxygen species (mtROS) and DNA (mtDNA) leakage.
- This process inhibited oxidative damage and the cGAS-mediated inflammatory response, thereby resolving foamy macrophage senescence.
Conclusions:
- Tramiprosate (TMP) effectively targets mitochondrial dysfunction-induced macrophage senescence post-SCI.
- TMP presents a promising therapeutic candidate for SCI, leveraging its blood-brain barrier permeability and established safety profile.
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