The Importance of Mitophagy in Maintaining Mitochondrial Function in U373MG Cells. Bafilomycin A1 Restores Aminochrome-Induced Mitochondrial Damage
Abstract
Aminochrome, an orthoquinone formed during the dopamine oxidation of neuromelanin, is neurotoxic because it induces mitochondria dysfunction, protein degradation dysfunction (both autophagy and proteasomal systems), α-synuclein aggregation to neurotoxic oligomers, neuroinflammation, and oxidative and endoplasmic reticulum stress. In this study, we investigated the relationship between aminochrome-induced autophagy/lysosome dysfunction and mitochondrial dysfunction in U373MGsiGST6 cells. Aminochrome (75 μM) induces mitochondrial dysfunction as determined by (i) a significant decrease in ATP levels (70%; P < 0.001) and (ii) a significant decrease in mitochondrial membrane potential (P < 0.001). Interestingly, the pretreatment of U373MGsiGST6 cells with 100 nM bafilomycin-A1, an inhibitor of lysosomal vacuolar-type H+-ATPase, restores ATP levels, mitochondrial membrane potential, and mitophagy, and decreases cell death. These results reveal (i) the importance of macroautophagy/the lysosomal degradation system for the normal functioning of mitochondria and for cell survival, and (ii) aminochrome-induced lysosomal dysfunction depends on the aminochrome-dependent inactivation of the vacuolar-type H+-ATPase, which pumps protons into the lysosomes. This study also supports the proposed protective role of glutathione transferase mu2–2 (GSTM2) in astrocytes against aminochrome toxicity, mediated by mitochondrial and lysosomal dysfunction.
Cited By
This article is cited by 30 publications.
- Hao Wu, Yajun Zhai, Jing Yu, Liping Wei, Xin Qi. Transcriptome and proteome analyses reveal that upregulation of GSTM2 by allisartan improves cardiac remodeling and dysfunction in hypertensive rats. Experimental and Therapeutic Medicine 2024, 27 (5) https://doi.org/10.3892/etm.2024.12508
- Sandro Huenchuguala, Juan Segura-Aguilar. Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease. Neural Regeneration Research 2024, 19 (3) , 529-535. https://doi.org/10.4103/1673-5374.380878
- Abdeslam Chagraoui, Youssef Anouar, Philippe De Deurwaerdere, Hugo R. Arias. To what extent may aminochrome increase the vulnerability of dopaminergic neurons in the context of Parkinson's disease. The International Journal of Biochemistry & Cell Biology 2024, 168 , 106528. https://doi.org/10.1016/j.biocel.2024.106528
- Fillipe Mendes De Araújo, Annyta Fernandes Frota, Lívia Bacelar de Jesus, Ticiane Caribe Macedo, Lorena Cuenca-Bermejo, Consuelo Sanchez-Rodrigo, Kariny Maria Silva Ferreira, Juciele Valéria Ribeiro de Oliveira, Maria de Fatima Dias Costa, Juan Segura-Aguilar, Silvia Lima Costa, Maria Trinidad Herrero, Victor Diógenes Amaral Silva. Aminochrome Induces Neuroinflammation and Dopaminergic Neuronal Loss: A New Preclinical Model to Find Anti-inflammatory and Neuroprotective Drugs for Parkinson’s Disease. Cellular and Molecular Neurobiology 2023, 43 (1) , 265-281. https://doi.org/10.1007/s10571-021-01173-5
- Cleonice Creusa Santos, Thyago R. Cardim-Pires, Liana Shvachiy, Luis Arturo Fonseca-Fonseca, Patricia Muñoz, Áurea Maria A. N. Almeida, Ana Carla S. Costa, Jéssica Teles-Souza, Estael Ochoa-Rodríguez, Maria de Fátima Dias Costa, Fernando L. Palhano, Juan Segura-Aguilar, Deyse B. Barbosa, Mayra R. do Bomfim, Manoelito C. dos Santos Junior, Franco Henrique A. Leite, Samuel Silva da Rocha Pita, Silvia Lima Costa, Yanier Núñez-Figueredo, Tiago Fleming Outeiro, Débora Foguel, Victor Diogenes Amaral Silva. JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species. Neurotoxicity Research 2022, 40 (6) , 2135-2147. https://doi.org/10.1007/s12640-022-00559-7
- Yi Jin, Yanjie Tan, Pengxiang Zhao, Yu Guo, Shilin Chen, Jian Wu, Zhuqing Ren. Glutathione S-transferase Mu 2 inhibits hepatic steatosis via ASK1 suppression. Communications Biology 2022, 5 (1) https://doi.org/10.1038/s42003-022-03251-w
- Juan Segura-Aguilar, Patricia Muñoz, Jose Inzunza, Mukesh Varshney, Ivan Nalvarte, Bengt Mannervik. Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase. Antioxidants 2022, 11 (2) , 296. https://doi.org/10.3390/antiox11020296
- Juan Segura-Aguilar, Irmgard Paris. Mechanisms of Dopamine Oxidation and Parkinson’s Disease. 2022, 1-36. https://doi.org/10.1007/978-3-030-71519-9_16-1
- Juan Segura-Aguilar, Ulises Ahumada-Castro, Irmgard Paris. Dopamine and L-Dopa as Selective Endogenous Neurotoxins. 2022, 1-35. https://doi.org/10.1007/978-3-030-71519-9_70-1
- Juan Segura-Aguilar, Irmgard Paris. Mechanisms of Dopamine Oxidation and Parkinson’s Disease. 2022, 1433-1468. https://doi.org/10.1007/978-3-031-15080-7_16
- Juan Segura-Aguilar, Ulises Ahumada-Castro, Irmgard Paris. Dopamine and L-Dopa as Selective Endogenous Neurotoxins. 2022, 255-289. https://doi.org/10.1007/978-3-031-15080-7_70
- Juan Segura-Aguilar, Bengt Mannervik, José Inzunza, Mukesh Varshney, Ivan Nalvarte, Patricia Muñoz. Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity. Neural Regeneration Research 2022, 17 (9) , 1861. https://doi.org/10.4103/1673-5374.335690
- Dongtao Lin, Yudan Zeng, Deyu Tang, Yongming Cai, . Study on the Mechanism of Liuwei Dihuang Pills in Treating Parkinson’s Disease Based on Network Pharmacology. BioMed Research International 2021, 2021 , 1-12. https://doi.org/10.1155/2021/4490081
- Ajay Kesharwani, Karin Schwarz, Ekta Dembla, Mayur Dembla, Frank Schmitz. Early Changes in Exo- and Endocytosis in the EAE Mouse Model of Multiple Sclerosis Correlate with Decreased Synaptic Ribbon Size and Reduced Ribbon-Associated Vesicle Pools in Rod Photoreceptor Synapses. International Journal of Molecular Sciences 2021, 22 (19) , 10789. https://doi.org/10.3390/ijms221910789
- Raúl Valdes, Alicia Armijo, Patricia Muñoz, Kjell Hultenby, Andres Hagg, Jose Inzunza, Ivan Nalvarte, Mukesh Varshney, Bengt Mannervik, Juan Segura-Aguilar. Cellular Trafficking of Glutathione Transferase M2-2 Between U373MG and SHSY-S7 Cells is Mediated by Exosomes. Neurotoxicity Research 2021, 39 (2) , 182-190. https://doi.org/10.1007/s12640-020-00327-5
- Shuang Zhang, Qiang Chu, Zhang Zhang, Yingfei Xu, Xiali Mao, Mingkui Zhang. Responses of Caenorhabditis elegans to various surface modifications of alumina nanoparticles. Environmental Pollution 2021, 271 , 116335. https://doi.org/10.1016/j.envpol.2020.116335
- Juan Segura-Aguilar. Neuroprotective mechanisms against dopamine oxidation-dependent neurotoxicity. 2021, 229-240. https://doi.org/10.1016/B978-0-12-822120-4.00005-8
- Juan Segura-Aguilar. Preclinical models based on endogenous neurotoxins. 2021, 263-282. https://doi.org/10.1016/B978-0-12-822120-4.00011-3
- Cleonice Creusa Santos, Patricia Muñoz, Áurea Maria A. N. Almeida, Juceni Pereira de Lima David, Jorge Mauricio David, Silvia Lima Costa, Juan Segura-Aguilar, Victor Diogenes Amaral Silva. The Flavonoid Agathisflavone from Poincianella pyramidalis Prevents Aminochrome Neurotoxicity. Neurotoxicity Research 2020, 38 (3) , 579-584. https://doi.org/10.1007/s12640-020-00237-6
- Wei-wei Wang, Jing Wang, Hai-jun Zhang, Shu-geng Wu, Guang-hai Qi. Transcriptome analysis reveals mechanism underlying the differential intestinal functionality of laying hens in the late phase and peak phase of production. BMC Genomics 2019, 20 (1) https://doi.org/10.1186/s12864-019-6320-y
- Juan Segura-Aguilar. The importance of choosing a preclinical model that reflects what happens in Parkinson's disease. Neurochemistry International 2019, 126 , 203-209. https://doi.org/10.1016/j.neuint.2019.03.016
- Juan Segura-Aguilar. On the Role of Aminochrome in Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Parkinson's Disease. Frontiers in Neuroscience 2019, 13 https://doi.org/10.3389/fnins.2019.00271
- Yaoyao Xia, Siyuan Chen, Sijing Zeng, Yuanyuan Zhao, Congrui Zhu, Baichuan Deng, Guoqiang Zhu, Yulong Yin, Wence Wang, Rüdiger Hardeland, Wenkai Ren. Melatonin in macrophage biology: Current understanding and future perspectives. Journal of Pineal Research 2019, 66 (2) https://doi.org/10.1111/jpi.12547
- Sandro Huenchuguala, Birgitta Sjödin, Bengt Mannervik, Juan Segura-Aguilar. Novel Alpha-Synuclein Oligomers Formed with the Aminochrome-Glutathione Conjugate Are Not Neurotoxic. Neurotoxicity Research 2019, 35 (2) , 432-440. https://doi.org/10.1007/s12640-018-9969-0
- Marianne O. Klein, Daniella S. Battagello, Ariel R. Cardoso, David N. Hauser, Jackson C. Bittencourt, Ricardo G. Correa. Dopamine: Functions, Signaling, and Association with Neurological Diseases. Cellular and Molecular Neurobiology 2019, 39 (1) , 31-59. https://doi.org/10.1007/s10571-018-0632-3
- Catalina Meléndez, Patricia Muñoz, Juan Segura-Aguilar. DT-Diaphorase Prevents Aminochrome-Induced Lysosome Dysfunction in SH-SY5Y Cells. Neurotoxicity Research 2019, 35 (1) , 255-259. https://doi.org/10.1007/s12640-018-9953-8
- Juan Segura-Aguilar. Neurotoxins as Preclinical Models for Parkinson’s Disease. Neurotoxicity Research 2018, 34 (4) , 870-877. https://doi.org/10.1007/s12640-017-9856-0
- Juan Segura-Aguilar. Comment on: “Activating Autophagy as a Therapeutic Strategy for Parkinson’s Disease”. CNS Drugs 2018, 32 (7) , 685-686. https://doi.org/10.1007/s40263-018-0533-5
- Juan Segura-Aguilar, Sandro Huenchuguala. Aminochrome Induces Irreversible Mitochondrial Dysfunction by Inducing Autophagy Dysfunction in Parkinson's Disease. Frontiers in Neuroscience 2018, 12 https://doi.org/10.3389/fnins.2018.00106
- Yu Zhao, Yinfeng Guo, Yuteng Jiang, Xiaodong Zhu, Yuqiu Liu, Xiaoliang Zhang. Mitophagy regulates macrophage phenotype in diabetic nephropathy rats. Biochemical and Biophysical Research Communications 2017, 494 (1-2) , 42-50. https://doi.org/10.1016/j.bbrc.2017.10.088