Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation

Abstract

While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.

Keywords: MCU; NCLX; electron transport chain; mitochondrial dysfunction; mitochondrial permeability transition pores; oxidative phosphorylation.

Figure 1 –. ETC and Ca²⁺ signaling overview.

MCU imports Ca²⁺ which is known to activate the following enzymes: PDH phosphatase, Isocitrate dehydrogenase (IDH), and α-ketoglutarate dehydrogenase (AKGDH). Export mechanisms include LETM1, TMBIM5, and NCLX. Known pathways are shown in solid arrows. Newer mechanisms involve Complex I, CoQ, complex IV, and ATP Synthase, shown in dashed arrows.

FIGURE 2 –. New mechanisms involving mitochondrial Ca²⁺.

(A) CLIPT – Complex I interacts with MCU and maintains its protein turnover rate. (Adapted from ref. (68)) (B) Complex IV subunit COX7RP is estrogen dependent, sits at the interface between Complex III and IV, and promotes supercomplex assembly and respiratory efficiency. Increasing COX7RP led to reduced mitochondrial Ca²⁺ and ROS, whereas inhibiting its expression produced the opposite effects (see ref. (86)). (C) Deactivated complex I promotes matrix acidification which dissolve CaP precipitates. The increased matrix Ca²⁺ triggers NCLX to exchange Ca²⁺ for Na⁺. Increased matrix Na⁺ decreases IMM fluidity and prevents CoQ diffusion, decreasing oxphos at Complex II + III. (Adapted from ref. (103)) (D) MCU binds to the subunit c of ATP Synthase in Trypanosoma (see ref. (92)). Excess Ca²⁺ may trigger rearrangement of the F₁ component of the ATP synthase to produce channels in the membrane component (see ref. (108)).