Nobiletin attenuates neurotoxic mitochondrial calcium overload through K⁺ influx and ΔΨ(m) across mitochondrial inner membrane.
10.4196/kjpp.2018.22.3.311
- Author:
Ji Hyung LEE
1
;
Khulan AMARSANAA
;
Jinji WU
;
Sang Chan JEON
;
Yanji CUI
;
Sung Cherl JUNG
;
Deok Bae PARK
;
Se Jae KIM
;
Sang Heon HAN
;
Hyun Wook KIM
;
Im Joo RHYU
;
Su Yong EUN
Author Information
1. Department of Physiology, Jeju National University, Jeju 63243, Korea. syeun@jejunu.ac.kr
- Publication Type:Original Article
- Keywords:
Calcium;
Mitochondrial calcium;
Mitochondrial K⁺ channels;
Mitochondrial membrane potential;
Nobiletin
- MeSH:
Animals;
Brain;
Calcium*;
Cell Death;
Cell Survival;
Citrus;
Fluorescence;
Fluorometry;
Glutamic Acid;
Membrane Potential, Mitochondrial;
Membrane Potentials;
Membranes*;
Mitochondria;
Neurodegenerative Diseases;
Neurons;
Neuroprotective Agents;
Rats;
Reactive Oxygen Species
- From:The Korean Journal of Physiology and Pharmacology
2018;22(3):311-319
- CountryRepublic of Korea
- Language:English
-
Abstract:
Mitochondrial calcium overload is a crucial event in determining the fate of neuronal cell survival and death, implicated in pathogenesis of neurodegenerative diseases. One of the driving forces of calcium influx into mitochondria is mitochondria membrane potential (ΔΨ(m)). Therefore, pharmacological manipulation of ΔΨ(m) can be a promising strategy to prevent neuronal cell death against brain insults. Based on these issues, we investigated here whether nobiletin, a Citrus polymethoxylated flavone, prevents neurotoxic neuronal calcium overload and cell death via regulating basal ΔΨ(m) against neuronal insult in primary cortical neurons and pure brain mitochondria isolated from rat cortices. Results demonstrated that nobiletin treatment significantly increased cell viability against glutamate toxicity (100 µM, 20 min) in primary cortical neurons. Real-time imaging-based fluorometry data reveal that nobiletin evokes partial mitochondrial depolarization in these neurons. Nobiletin markedly attenuated mitochondrial calcium overload and reactive oxygen species (ROS) generation in glutamate (100 µM)-stimulated cortical neurons and isolated pure mitochondria exposed to high concentration of Ca²⁺ (5 µM). Nobiletin-induced partial mitochondrial depolarization in intact neurons was confirmed in isolated brain mitochondria using a fluorescence microplate reader. Nobiletin effects on basal ΔΨ(m) were completely abolished in K⁺-free medium on pure isolated mitochondria. Taken together, results demonstrate that K⁺ influx into mitochondria is critically involved in partial mitochondrial depolarization-related neuroprotective effect of nobiletin. Nobiletin-induced mitochondrial K⁺ influx is probably mediated, at least in part, by activation of mitochondrial K⁺ channels. However, further detailed studies should be conducted to determine exact molecular targets of nobiletin in mitochondria.
