Microglial tunneling nanotubes: an intercellular transfer facilitating mitochondrial dysfunction and neuroinflammation in experimental cerebral malaria.

Authors

Yan Shen, Yi Wang, Chao Yang, Jun Wang, Yuxiao Huang, Qinghao Zhu, Ganze Li, Tong Li, Jiayi Sun, Jie Ren, Xiaolin Chen, Shuhan Xing, Sijia Wen, Yinghui Li, Jiao Liang, Ya Zhao

Published in

Apoptosis : an international journal on programmed cell death. Volume 31. Issue 7. Jul 01, 2026. Epub Jul 01, 2026.

Abstract

Cerebral malaria (CM), the most severe neurological manifestation of Plasmodium infection, is characterized by microglial activation that plays a pivotal role in initiating pathogenic neuroinflammatory cascades. Tunneling nanotubes (TNTs) are dynamic F-actin-based intercellular connections which transfer mitochondria and pathogenic factors. Although TNTs have been implicated in various neuropathological conditions, their precise involvement in CM pathogenesis, particularly in relation to microglial activation, remains undefined. In this study, single-cell RNA-sequencing (scRNA-seq) revealed significant dysregulation of TNT-associated genes and actin cytoskeleton pathway remodeling in microglia of ECM model. In vitro studies demonstrated that Plasmodium-infected red blood cells (pRBCs)-stimulated primary microglia formed extensive F-actin-rich tunneling nanotubes, which mediated the bidirectional transfer for mitochondria and facilitated intercellular trafficking of lysosomal contents and malarial pigment. These TNT-mediated intercellular communication amplified microglial activation, as evidenced by: (i) lipid peroxidation, (ii) mitochondrial dysfunction, and (iii) autophagosome (LC3⁺) accumulation. This process further amplifies neuroinflammation through TNFα/IL-6 secretion and expansion of CD45^high microglial populations. Pharmacological TNT inhibition restores microglial homeostasis in ECM model. In conclusion, TNTs mediate neuroinflammation in the ECM model by transferring mitochondria and malarial pigment between microglia. Although mitochondrial transfer may transiently support cellular homeostasis, progressive malarial pigment accumulation triggers lipid metabolism dysregulation and amplified neuroinflammation. Inhibiting TNTs formation attenuates microglial hyperactivation, highlighting targeted regulation of TNT-mediated intercellular communication as a potential therapeutic approach for CM-associated neuropathology.

PMID:
42387204
Bibliographic data and abstract were imported from PubMed on 02 Jul 2026.

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