1. Mitochonic acid-5 attenuates TNF-α-mediated neuronal inflammation via activating Parkin-related mitophagy and augmenting the AMPK-Sirt3 pathways.
- Author
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Huang D, Liu M, and Jiang Y
- Subjects
- Adenylate Kinase metabolism, Animals, Antioxidants metabolism, Apoptosis drug effects, Cell Line, Energy Metabolism drug effects, Mice, Mitochondria drug effects, Mitochondria metabolism, Neurons drug effects, Neurons metabolism, Oxidation-Reduction, Stress, Physiological drug effects, Up-Regulation drug effects, Indoleacetic Acids pharmacology, Inflammation pathology, Mitophagy drug effects, Neurons pathology, Phenylbutyrates pharmacology, Signal Transduction drug effects, Sirtuin 3 metabolism, Tumor Necrosis Factor-alpha toxicity, Ubiquitin-Protein Ligases metabolism
- Abstract
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., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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