Mitochondrial Calcium Signalling: Role in Oxidative Phosphorylation Diseases

Abstract

Mitochondria are double membrane-bound organelles that not only constitute the “cellular power plants” but also are crucially involved in cell survival, apoptosis, redox control, Ca2+ homeostasis and many metabolic and biosynthetic pathways. The mitochondria generate energy by oxidizing hydrogen derived from dietary carbohydrate (TCA: tricarboxylic acid cycle) and lipids (beta-oxidation) with oxygen to generate heat and energy in the form of ATP (Adenosine triphosphate). Energy generation in mitochondria occurs primarily through oxidative phosphorylation (OXPHOS), a process in which electrons are passed along a series of carrier molecules called the electron transport chain (ETC). This chain is composed of four multisubunit assemblies that are embedded in the mitochondrial inner membrane: complex I (NADH:ubiquinone oxidoreductase; EC 1.6.5.3), complex II (succinate:ubiquinone oxidoreductase; EC 1.3.5.1), complex III (ubiquinol:cytochrome-c oxidoreductase; EC 1.10.2.2) and complex IV (cytochrome-c oxidase; EC1.9.3.1). Complexes I, III and IV actively translocate protons from the matrix into the intermembrane space using energy extracted from electrons passing through the chain. These electrons are liberated from NADH and FADH2, at complexes I and II, respectively, where they are donated to the lipophilic electron carrier coenzyme Q for further transport to complex III. From there, electrons are shuttled to complex IV by cytochrome-c. At this complex, electrons are finally used for the reduction of oxygen to water (Hatefi, 1985; Saraste, 1999) (Figure 1 A). The energy released by the flow of electrons through the ETC and the flux of protons out of the mitochondrial inner membrane creates a capacitance across the mitochondrial inner membrane, the electrochemical gradient (∆P) composed of an electrical potential (Δψ) and a concentration ratio (ΔpH). The potential energy stored in ∆P is coupled to ATP synthesis by complex V (F0/F1-ATP-synthase; EC 3.6.1.34). As protons flow back into mitochondrial