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Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy

Authors :
Cailin Wang
Xiufeng Wang
Shangqi Sun
Yanmin Chang
Piaopiao Lian
Hongxiu Guo
Siyi Zheng
Rong Ma
Gang Li
Source :
Immunity & Ageing, Vol 21, Iss 1, Pp 1-15 (2024)
Publication Year :
2024
Publisher :
BMC, 2024.

Abstract

Abstract Background The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies. Methods To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms. Result We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM. Conclusion Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

Details

Language :
English
ISSN :
17424933
Volume :
21
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Immunity & Ageing
Publication Type :
Academic Journal
Accession number :
edsdoj.3f7a363a1d43e6a73262dc359e05f3
Document Type :
article
Full Text :
https://doi.org/10.1186/s12979-024-00437-0