Journal Article

Irisin regulates oxidative stress and mitochondrial dysfunction through the UCP2-AMPK pathway in prion diseases

Yang, Dongming, Zhao, Mengyang, Wang, Jingjing, Zhao, Deming, Li, Jie, Gou, Fengting, Sun, Zhixin, Dai, Yuexin, Wen, Pei, Li, Zhiping, Yang, Lifeng, Wang, DongDong

2025

Overview

Prion diseases are a group of fatal neurodegenerative disorders characterized by the abnormal folding of cellular prion proteins into pathogenic forms. The development of these diseases is intricately linked to oxidative stress and mitochondrial dysfunction. Irisin, an endogenous myokine, has demonstrated considerable neuroprotective potential due to its antioxidative properties. However, the protective effects of irisin against prion diseases have yet to be clarified. Our findings indicate that treatment with exogenous irisin can mitigate the apoptosis induced by PrP 106–126. Additionally, irisin significantly reduces oxidative stress and alleviates the mitochondrial dysfunction triggered by PrP 106–126 . Furthermore, irisin treatment targets uncoupling protein 2 (UCP2) and activates the AMPK-Nrf2 pathway, substantially improving oxidative stress and mitochondrial dysfunction in N2a cells induced by PrP 106–126 . These results suggest that irisin represents a novel and promising therapeutic approach for treating prion diseases. Highlights PrP 106–126 induces mitochondrial dysfunction in a mtROS-dependent manner. Irisin alleviates PrP 106–126 -induced oxidative stress via UCP2 activation. UCP2 mediates irisin-induced AMPK-Nrf2 activation. Inhibition of oxidative stress rescues PrP 106–126 -induced cell death. PrP 106–126 exposure induces ROS accumulation, leading to mitochondrial dysfunction and cell death. Irisin has a protective effect against PrP 106–126 toxicity and depends on the activation of the UCP2-AMPK signaling pathway.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/109 / 13/2 / 13/31 / 13/95 / 14 / 14/1 / 14/19 / 14/28 / 14/34 / 631/80/304 / 631/80/82/23 / AMP-Activated Protein Kinases - metabolism / Animals / Antibodies / Apoptosis / Apoptosis - drug effects / Biochemistry / Biomedical and Life Sciences / Cell activation / Cell Biology / Cell Culture / Cell death / Fibronectins - metabolism / Fibronectins - pharmacology / Humans / Immunology / Life Sciences / Mice / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial uncoupling protein 2 / Neurodegenerative diseases / Neuroprotection / NF-E2-Related Factor 2 - metabolism / Oxidative stress / Oxidative Stress - drug effects / Peptide Fragments / Prion Diseases - genetics / Prion Diseases - metabolism / Prion Diseases - pathology / Prion protein / Prions - metabolism / Signal Transduction - drug effects / Uncoupling Protein 2 - genetics / Uncoupling Protein 2 - metabolism