Scholarlink

<p>Persistent neuroinflammation is a hallmark of central nervous system (CNS) injury, driving neuronal loss and functional deficits. While microglial lipid metabolic reprogramming, particularly lipid droplet accumulation, has been implicated in chronic inflammation, the underlying mechanisms remain poorly understood. Using single-cell transcriptomics, we identified a previously defined lipid droplet-accumulating microglia (LDAM) subpopulation in spinal cord injury (SCI), characterized by elevated PLIN2 expression. Genetic deletion of <i>Plin2</i> markedly reduced lipid droplet burden, attenuated neuroinflammation, and promoted neuronal survival and functional recovery in vivo. Mechanistically, PLIN2 interacts with the mitochondrial outer membrane protein PGAM5 to regulate lipid droplet-mitochondria contacts. This interaction inverts canonical metabolic flux by redirecting fatty acids from mitochondria back to lipid droplets, thereby suppressing β-oxidation and inducing mitochondrial dysfunction, which subsequently triggers STING-dependent inflammation. Notably, the PLIN2 220-392 domain is essential for PGAM5 binding and contact formation; disrupting this interaction attenuates STING signaling and enhances neuroprotection and functional recovery in vivo. Our findings identify the PLIN2-PGAM5 as a critical metabolic-immune pathway and suggest that targeting organelle-contact-mediated metabolic reprogramming represents a potential therapeutic strategy for CNS injury.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

PLIN2-PGAM5-regulated lipid droplet-mitochondria contacts drive microglial neuroinflammation after spinal cord injury via fatty acid metabolic reprogramming

  • 期刊论文

  • 发表日期：

    2026年7月24日

查看全文
  • Daoqiang Huang,
  • Hong Li,
  • Yiqian Luo,
  • Pan Jiang,
  • Haojie Zhang,
  • Dingzhong Cheng,
  • Longyou Xiao,
  • Kuileung Tong,
  • Jiale He,
  • Zengbo Lu,
  • Xuantao Hu,
  • Mao Pang,
  • Senyu Yao,
  • Limin Rong,
  • Bin Liu

摘要

Persistent neuroinflammation is a hallmark of central nervous system (CNS) injury, driving neuronal loss and functional deficits. While microglial lipid metabolic reprogramming, particularly lipid droplet accumulation, has been implicated in chronic inflammation, the underlying mechanisms remain poorly understood. Using single-cell transcriptomics, we identified a previously defined lipid droplet-accumulating microglia (LDAM) subpopulation in spinal cord injury (SCI), characterized by elevated PLIN2 expression. Genetic deletion of Plin2 markedly reduced lipid droplet burden, attenuated neuroinflammation, and promoted neuronal survival and functional recovery in vivo. Mechanistically, PLIN2 interacts with the mitochondrial outer membrane protein PGAM5 to regulate lipid droplet-mitochondria contacts. This interaction inverts canonical metabolic flux by redirecting fatty acids from mitochondria back to lipid droplets, thereby suppressing β-oxidation and inducing mitochondrial dysfunction, which subsequently triggers STING-dependent inflammation. Notably, the PLIN2 220-392 domain is essential for PGAM5 binding and contact formation; disrupting this interaction attenuates STING signaling and enhances neuroprotection and functional recovery in vivo. Our findings identify the PLIN2-PGAM5 as a critical metabolic-immune pathway and suggest that targeting organelle-contact-mediated metabolic reprogramming represents a potential therapeutic strategy for CNS injury.