Intracellular magnesium level determines cell viability in the MPP+ model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder resulting from mitochondrial dysfunction in dopaminergic neurons. Mitochondria are believed to be responsible for cellular Mg²⁺ homeostasis. Mg²⁺ is indispensable for maintaining ordinal cellular functions, hence perturbation of the cellular Mg²⁺ homeostasis may be responsible for the disorders of physiological functions and diseases including PD. However, the changes in intracellular Mg²⁺ concentration ([Mg²⁺]i) and the role of Mg²⁺ in PD have still been obscure. In this study, we investigated [Mg²⁺]i and its effect on neurodegeneration in the 1-methyl-4-phenylpyridinium (MPP⁺) model of PD in differentiated PC12 cells. Application of MPP⁺ induced an increase in [Mg²⁺]i immediately via two different pathways: Mg²⁺ release from mitochondria and Mg²⁺ influx across cell membrane, and the increased [Mg²⁺]i sustained for more than 16 h after MPP⁺ application. Suppression of Mg²⁺ influx decreased the viability of the cells exposed to MPP⁺. The cell viability correlated highly with [Mg²⁺]i. In the PC12 cells with suppressed Mg²⁺ influx, ATP concentration decreased and the amount of reactive oxygen species (ROS) increased after an 8h exposure to MPP⁺. Our results indicate that the increase in [Mg²⁺]i inhibited cellular ROS generation and maintained ATP production, which resulted in the protection from MPP⁺ toxicity.

Mitochondrial Mg2+ homeostasis decides cellular energy metabolism and vulnerability to stress

“…6 ). In contrast, in a cellular model experiments of Parkinson’s disease, increase in [Mg 2+ ] cyto , which probably links to [Mg 2+ ] mito increase, protects cells from neurodegeneration by maintaining cellular ATP concentration and suppressing ROS production 28 . In summary, mitochondrial Mg 2+ regulate the cellular metabolic process via shift of mitochondrial energy metabolism, and it changes mitochondrial morphology and affects the cell viability through changing stress susceptibility.…”

“…To reveal the regulatory mechanism of intracellular Mg 2+ , we have developed Mg 2+ sensitive fluorescence probes and imaging techniques 20 21 22 23 24 . These intracellular Mg 2+ imaging works revealed Mg 2+ mobilization in pathological and physiological conditions 25 26 27 28 , and mitochondria are intracellular Mg 2+ stores 29 . Mitochondria redistribute cytosolic and mitochondrial Mg 2+ sufficient to change the cytosolic Mg 2+ concentration ([Mg 2+ ] cyto ) in response to several physiological stimuli 25 26 .…”

Elevated circulating magnesium levels in patients with Parkinson’s disease: a meta-analysis

“… 17 , 18 Disturbances in Mg homeostasis have been implicated in a broad spectrum of neurodegenerative disorders of aging, including PD and Alzheimer’s disease. 19 , 20 Numerous studies pointed out the possible role of Mg levels in patients with PD, but the conclusions were ambiguous and inconsistent. Several studies have shown that systemic Mg levels were reduced in PD patients compared with healthy controls (HC).…”

Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions

“…It is estimated that ϳ4 -5 mM of [Mg 2ϩ ] i in the cytosol exists as a complex with ATP in several types of mammalian cells (22). In a previous report (23), carbonyl cyanide p-(trifluorome-…”