Monitoring of glutamate‐induced excitotoxicity by mitochondrial oxygen consumption

Journal Article · Thu Sep 06 00:00:00 EDT 2018 · Synapse (New York)

DOI:https://doi.org/10.1002/syn.22067· OSTI ID:1482129

Kumagai, Ayako ^[1]; Sasaki, Tsutomu ^[2]; Matsuoka, Kenta ^[3]; Abe, Masayoshi ^[3]; Tabata, Toshihide ^[3]; Itoh, Yumi ^[4]; Fuchino, Hiroyuki ^[5]; Wugangerile, Sartagul ^[4]; Suga, Mika ^[6]; Yamaguchi, Tomoko ^[7]; Kawahara, Hidehisa ^[8]; Nagaoka, Yasuo ^[8]; Kawabata, Kenji ^[7]; Furue, Miho Kusuda ^[6]; Takemori, Hiroshi  ^[9]

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1. Cell Signaling and Metabolic Disease National Institute of Biomedical Innovation, Health and Nutrition Osaka Japan, Life Science and Biotechnology, Chemistry, Materials and Bioengineering Kansai University Osaka Japan
2. Department of Neurology Osaka University Graduate School of Medicine Osaka Japan
3. Laboratory for Biological Information Processing, Graduate School of, Science and Engineering University of Toyama Toyama Japan
4. Cell Signaling and Metabolic Disease National Institute of Biomedical Innovation, Health and Nutrition Osaka Japan
5. Research Center for Medicinal Plant Resources, Tukuba Division National Institutes of Biomedical Innovation, Health and Nutrition Tsukuba Japan
6. Stem Cell Cultures National Institutes of Biomedical Innovation, Health and Nutrition Osaka Japan
7. Stem Cell Regulation National Institutes of Biomedical Innovation, Health and Nutrition Osaka Japan
8. Life Science and Biotechnology, Chemistry, Materials and Bioengineering Kansai University Osaka Japan
9. Cell Signaling and Metabolic Disease National Institute of Biomedical Innovation, Health and Nutrition Osaka Japan, Faculty of Engineering, Depaetment of Chemistry and Biomolecular Science Gifu University Gifu Japan

Abstract Dysfunction of mitochondrial activity is often associated with the onset and progress of neurodegenerative diseases. Membrane depolarization induced by Na ⁺ influx increases intracellular Ca ²⁺ levels in neurons, which upregulates mitochondrial activity. However, overlimit of Na ⁺ influx and its prolonged retention ultimately cause excitotoxicity leading to neuronal cell death. To return the membrane potential to the normal level, Na ⁺ /K ⁺ ‐ATPase exchanges intracellular Na ⁺ with extracellular K ⁺ by consuming a large amount of ATP. This is a reason why mitochondria are important for maintaining neurons. In addition, astrocytes are thought to be important for supporting neighboring neurons by acting as energy providers and eliminators of excessive neurotransmitters. In this study, we examined the meaning of changes in the mitochondrial oxygen consumption rate (OCR) in primary mouse neuronal populations. By varying the medium constituents and using channel modulators, we found that pyruvate rather than lactate supported OCR levels and conferred on neurons resistance to glutamate‐mediated excitotoxicity. Under a pyruvate‐restricted condition, our OCR monitoring could detect excitotoxicity induced by glutamate at only 10 μM. The OCR monitoring also revealed the contribution of the N‐methyl‐D‐aspartate receptor and Na ⁺ /K ⁺ ‐ATPase to the toxicity, which allowed evaluating spontaneous excitation. In addition, the OCR monitoring showed that astrocytes preferentially used glutamate, not glutamine, for a substrate of the tricarboxylic acid cycle. This mechanism may be coupled with astrocyte‐dependent protection of neurons from glutamate‐mediated excitotoxicity. These results suggest that OCR monitoring would provide a new powerful tool to analyze the mechanisms underlying neurotoxicity and protection against it.

• Sponsoring Organization: USDOE
• OSTI ID: 1482129
• Journal Information: Synapse (New York), Journal Name: Synapse (New York) Vol. 73 Journal Issue: 1; ISSN 0887-4476
• Publisher: Wiley Blackwell (John Wiley & Sons)
• Country of Publication: United States
• Language: English