Abstract
Cellular energy production processes are composed of many Mg2+ dependent enzymatic reactions. In fact, dysregulation of Mg2+ homeostasis is involved in various cellular malfunctions and diseases. Recently, mitochondria, energy-producing organelles, have been known as major intracellular Mg2+ stores. Several biological stimuli alter mitochondrial Mg2+ concentration by intracellular redistribution. However, in living cells, whether mitochondrial Mg2+ alteration affect cellular energy metabolism remains unclear. Mg2+ transporter of mitochondrial inner membrane MRS2 is an essential component of mitochondrial Mg2+ uptake system. Here, we comprehensively analyzed intracellular Mg2+ levels and energy metabolism in Mrs2 knockdown (KD) cells using fluorescence imaging and metabolome analysis. Dysregulation of mitochondrial Mg2+ homeostasis disrupted ATP production via shift of mitochondrial energy metabolism and morphology. Moreover, Mrs2 KD sensitized cellular tolerance against cellular stress. These results indicate regulation of mitochondrial Mg2+ via MRS2 critically decides cellular energy status and cell vulnerability via regulation of mitochondrial Mg2+ level in response to physiological stimuli.
Highlights
Cellular energy production processes are composed of many Mg2+ dependent enzymatic reactions
We investigated the importance of mitochondrial Mg2+ homeostasis by an RNAi-mediated Mrs[2] KD in HeLa cells
While Mag-Fura-2 is normally used for the measurement of [Mg2+]cyto (Fig. 1a–c), the co-localization of Mag-Fura-2 and a mitochondrial marker MitoFluor Red signals was observed after Mag-Fura-2 wash out from cytosol by digitonin treatment (Fig. 1d–f), indicating that this cell membrane permeabilization protocol by using Mag-Fura-2 enables mitochondrial Mg2+ measurement. [Mg2+]mito in Mrs[2] KD cells was lower than that in normal cells (Fig. 1g)
Summary
Cellular energy production processes are composed of many Mg2+ dependent enzymatic reactions. Mrs[2] KD sensitized cellular tolerance against cellular stress These results indicate regulation of mitochondrial Mg2+ via MRS2 critically decides cellular energy status and cell vulnerability via regulation of mitochondrial Mg2+ level in response to physiological stimuli. ATP binds to magnesium ion (Mg2+) to compose biologically functional form, and most of intracellular ATP and Mg2+ assumed to form Mg-ATP complexes Because both ATP and Mg2+ are mutually and strongly buffered in cytosol, it had been believed that Mg2+ deeply contributes on energy metabolism. Recent studies using novel Mg2+ fluorescent probe successfully visualized that mitochondrial Mg2+ concentration ([Mg2+]mito) dynamically changes[22,30] It is not clear, in cells, how the changes of [Mg2+]mito comprehensively affect the cellular energy metabolism in detail. Mg2+ uptake into mitochondria via MRS2 is essential for the maintenance of respiratory chain and cell viability[5]
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