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.

• Authors: Sandro Huenchuguala, Patricia Muñoz, Juan Segura-Aguilar
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 8 Issue 10 Pg. 2247-2253 (10 18 2017) ISSN: 1948-7193 [Electronic] United States
• PMID: 28763613 (Publication Type: Journal Article)

Chemical References

• Indolequinones
• Macrolides
• alpha-Synuclein
• aminochrome 1
• bafilomycin A1
• Dopamine

Topics

• Autophagy (physiology)
• Cell Line, Tumor
• Dopamine (metabolism)
• Humans
• Indolequinones (pharmacology)
• Lysosomes (metabolism)
• Macrolides (pharmacology)
• Membrane Potential, Mitochondrial (physiology)
• Mitochondria (drug effects, metabolism)
• Mitophagy (physiology)
• alpha-Synuclein (metabolism)