The destiny of Ca(2+) released by mitochondria

Abstract

Mitochondrial Ca(2+) is known to regulate diverse cellular functions, for example energy production and cell death, by modulating mitochondrial dehydrogenases, inducing production of reactive oxygen species, and opening mitochondrial permeability transition pores. In addition to the action of Ca(2+) within mitochondria, Ca(2+) released from mitochondria is also important in a variety of cellular functions. In the last 5 years, the molecules responsible for mitochondrial Ca(2+) dynamics have been identified: a mitochondrial Ca(2+) uniporter (MCU), a mitochondrial Na(+)-Ca(2+) exchanger (NCLX), and a candidate for a mitochondrial H(+)-Ca(2+) exchanger (Letm1). In this review, we focus on the mitochondrial Ca(2+) release system, and discuss its physiological and pathophysiological significance. Accumulating evidence suggests that the mitochondrial Ca(2+) release system is not only crucial in maintaining mitochondrial Ca(2+) homeostasis but also participates in the Ca(2+) crosstalk between mitochondria and the plasma membrane and between mitochondria and the endoplasmic/sarcoplasmic reticulum.

Fig. 1

Regulation of mitochondrial functions by mitochondrial Ca²⁺. Mitochondrial Ca²⁺ activates three dehydrogenases in the mitochondrial matrix: pyruvate dehydrogenase (PDHC), oxoglutarate dehydrogenase (OGDH), and isocitrate dehydrogenase (ICDH). ROS production is stimulated by increased mitochondrial Ca²⁺, possibly via increased NADH production. F1-Fo ATP synthase is activated by mitochondrial Ca²⁺, although this is still controversial. This regulatory activity contributes to energy homeostasis. PTP opening is activated by a large increase of mitochondrial Ca²⁺, resulting in the release of a variety of compounds from mitochondria, for example cytochrome c (cytc), pro-caspase, and Ca²⁺, leading to apoptosis or necrosis. CS citrate synthase, ACO aconitase, SCS succinyl-CoA synthase, SDH succinate dehydrogenase, FH fumarate hydratase, MDH malate dehydrogenase, SN F1-Fo ATP synthase, RR ruthenium red, MUni mitochondrial Ca²⁺ uniporter, mRyR mitochondrial RyR, mNCX mitochondrial Na⁺–Ca²⁺ exchanger, mHCX mitochondrial H⁺–Ca²⁺ exchanger

Fig. 2

Ca²⁺ communication between mitochondria and the plasma membrane and between mitochondria and the ER/SR

Fig. 3

Close location of mitochondria and the ER/SR in A20 B lymphocytes (a) and in HL-1 cardomyocytes (b). Cells were co-transfected with mitochondria-targeted pTagRFP-mito (red) and ER/SR-targeted cameleon D1ER (green). Images were acquired by use of a laser-scanning confocal microscope (LSM710, Carl Zeiss) with a ×63 oil objective lens, and 3D images were reconstructed by use of Imaris (Bitplane) (color figure online)

Fig. 4

Roles of NCLX in pancreatic β-cells (a), astrocytes (b), B lymphocytes (c), and cardiomyocytes (d). See text for details

Fig. 5

Modulation of SERCA activity by NCLX reduction in (a) DT40 B lymphocytes and (b) HL-1 cardiomyocytes. a ER Ca²⁺ uptake by wild type and NCLX^+/− DT40 cells. ER Ca²⁺ uptake were activated by applying 0.1 mM MgATP and 100 nM Ca²⁺ in Mag Fluo-4-loaded and permeabilized cells under conditions in which mitochondrial respiration was intact. The bar graph depicts the initial velocity of the ER Ca²⁺ increase. Data are mean ± SEM of independent recordings. Modified from Kim et al. [44]. b SR Ca²⁺ reuptake by HL-1 cardiomyocytes. Plasmid harbouring Cameleon D1ER, an indicator of SR Ca²⁺, was co-transfected with control (white) or NCLX siRNA (black) into HL-1 cardiomyoyctes. After emptying Ca²⁺ in SR with 10 mM caffeine, recovery of SR Ca²⁺ was measured. The bar graph depicts the recovery time constant τ, showing that SR Ca²⁺ reuptake was slower in NCLX knockdown cells. **p < 0.01, *p < 0.05. Modified from Takeuchi et al. [46]