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Mitochonic acid‐5 attenuates TNF‐α‐mediated neuronal inflammation via activating Parkin‐related mitophagy and augmenting the AMPK–Sirt3 pathways
Author(s) -
Huang Dezhi,
Liu Min,
Jiang Yugang
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28783
Subject(s) - parkin , mitophagy , ampk , inflammation , sirt3 , tumor necrosis factor alpha , autophagy , chemistry , pink1 , amp activated protein kinase , microbiology and biotechnology , pharmacology , medicine , endocrinology , biology , biochemistry , protein kinase a , sirtuin , kinase , apoptosis , enzyme , disease , parkinson's disease , nad+ kinase
Mitochondrial dysfunction has been found to be associated with neuronal inflammation; however, no effective drug is available to attenuate neuroinflammation via sustaining mitochondrial function. In the current study, experiments were performed to understand the beneficial effects of mitochonic acid 5 (MA‐5) on tumor necrosis factor‐α (TNF‐α)‐mediated neuronal injury and mitochondrial damage. Our data illustrated that MA‐5 pretreatment reduced inflammation response induced by TNF‐α in CATH.a cells. Molecular investigations demonstrated that MA‐5 pretreatment repressed oxidative stress, inhibited endoplasmic reticulum stress, sustained cellular energy metabolism, and blocked cell apoptosis induced by TNF‐α stress. Further, we found that MA‐5 treatment elevated the expression of Sirtuin 3 (Sirt3) and this effect was dependent on the activation of AMP‐activated protein kinase (AMPK) pathway. Blockade of AMPK abolished the promotive action of MA‐5 on Sirt3 and thus mediated mitochondrial damage and cell death. Besides, we also found that MA‐5 treatment augmented Parkin‐related mitophagy and increased mitophagy promoted CATH.a cells survival via improving mitochondrial function. Knockdown of Parkin abolished the beneficial action of MA‐5 on mitochondrial homeostasis and CATH.a cell survival. Altogether, our results confirm that MA‐5 is an effective drug to attenuate neuroinflammation via sustaining mitochondrial damage and promoting CATH.a cell survival. The protective action of MA‐5 on neuronal damage is associated with Parkin‐related mitophagy and the activation of AMPK–Sirt3 pathways.