The Involvement of Mg2+ in Regulation of Cellular and Mitochondrial Functions

Abstract

Mg²⁺ is an essential mineral with pleotropic impacts on cellular physiology and functions. It acts as a cofactor of several important enzymes, as a regulator of ion channels such as voltage-dependent Ca²⁺ channels and K⁺ channels and on Ca²⁺-binding proteins. In general, Mg²⁺ is considered as the main intracellular antagonist of Ca²⁺, which is an essential secondary messenger initiating or regulating a great number of cellular functions. This review examines the effects of Mg²⁺ on mitochondrial functions with a particular focus on energy metabolism, mitochondrial Ca²⁺ handling, and apoptosis.

Figure 1

Regulation of mitochondrial functions by Mg²⁺. Mitochondrial Mg²⁺ activates (------>) three dehydrogenases in the mitochondrial matrix: pyruvate dehydrogenase (conversion of mitochondrial pyruvate to acetyl coenzyme A), isocitrate dehydrogenase (conversion of isocitrate to 2-oxoglutarate), and 2-oxoglutarate dehydrogenase (conversion of 2-oxoglutarate to succinyl coenzyme A). In addition, mitochondrial Mg²⁺ activates F₀/F₁-ATP synthase, which is the terminal complex of mitochondrial oxidative phosphorylation (OXPHOS). This regulatory activity contributes to mitochondrial energy metabolism. Mitochondrial Mg²⁺ inhibits (------|) Ca²⁺ transporters localised in the inner mitochondrial membrane: Ca²⁺-dependent permeability transition pore (PTP) opening that results in the release of a variety of compounds from mitochondria including Ca²⁺, mitochondrial Ca²⁺ uniporter (MCU), mitochondrial ryanodine receptor (RyR), and mitochondrial Na⁺/Ca²⁺ exchanger (NCX). This regulatory activity contributes to both intracellular and mitochondrial Ca²⁺ homeostasis. Cytoplasmic Mg²⁺ regulates mitochondrial Bax/Bak-dependent apoptosis, which is regulated by proteins of the Bcl-2 family such as Bcl-X_L, Bcl-2. TCA: tricarboxylic acid cycle/Krebs cycle, ACoA: acetyl coenzyme A, C: citrate, IC: isocitrate, OG: 2-oxoglutarate, SC: succinyl coenzyme A, S: succinate, F: fumarate, M: malate, OA: oxaloacetate, RaM: rapid mode of mitochondrial Ca²⁺ uptake, HCX: mitochondrial H⁺/Ca²⁺ exchanger, SLC41A3: mitochondrial Mg²⁺ efflux system, Mrs2: mitochondrial Mg²⁺ influx channel, VDAC: voltage dependent anion channel.