Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts

Abstract

It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure–function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions—the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores.

Spatial and Functional Crosstalk between the Mitochondrial Na+-Ca2+ Exchanger NCLX and the Sarcoplasmic Reticulum Ca2+ Pump SERCA in Cardiomyocytes

“…On the other hand, it was predicted by the TopPred program [ 45 ] to possess one mitochondria transit peptide and 12 TMs whose C-terminus faced the opposite side of the long TM 5–6 loop, as presented in Cai and Lytton [ 46 ] and Kostic et al [ 47 ]. A recently developed AI-based 3D structure prediction tool, AlphaFold [ 24 ], showed a similar prediction [ 6 ]. The results obtained by a bimolecular fluorescence complementation assay ( Figure 1 ) support the latter prediction that the C-terminus of NCLX is facing the opposite side of the matrix.…”

“…In fact, NCLX-SERCA2B co-transfection pairs corresponding to pairs v-viii in the Figure 1A did not show any positive signals (see the light blue bars in Figure 1C). Regarding NCLX, the topology and the three-dimensional (3D) structure have not been clarified yet; however, a recently developed artificial intelligence (AI)-based structure prediction method, AlphaFold [24], visualized that the C-terminus of NCLX is facing the opposite side of the long regulatory loop that is hypothesized to face the matrix, while the N-terminus contains a putative mitochondria transit peptide, the destiny of which is still unknown (see pdb file AF-Q6J4K2-F1-model_v2 in AlphaFold Protein Structure Database, https://alphafold.ebi.ac.uk/ (accessed on 13 December 2021) and review [6]). From this prediction, it is strongly suggested that at least the C-terminus of NCLX is accessible to cytoplasmic space, making the fused truncated mKG-found in pairs ii, iv, vi, and viii in Figure 1A-possible to react with the complement half of the mKG fused with SERCAs.…”

“…The mitochondrial Ca 2+ in cardiomyocytes is balanced by an influx via the Ca 2+ uniport (CU mit ) activity and by an efflux via the Na + -Ca 2+ exchange (NCX mit ) or the H + -Ca 2+ exchange (HCX mit ) activities with the former plays the major part [3,4] (see also reviews [5][6][7]). It has been more than a decade since the molecules responsible for the activities were identified-MCU and its accessory proteins such as MICUs, EMRE, and so on for CU mit , NCLX for NCX mit , and possibly Letm1 for HCX mit -and the physiological/pathophysiological roles of these proteins in the heart have been extensively studied [8][9][10][11][12].…”

Mitochondrial Ca2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

“…The intracellular sodium concentration [Na + ]c has been shown to be increased in failing guinea pig hearts relative to [Na + ]c in normal hearts [ 25 , 48 , 265 ]. NCLX accelerates Ca 2+ outflow and reduces [Ca 2+ ]m in failing hearts [ 266 ]. In addition, the pharmacological inhibition of NCLX restored mitochondrial Ca 2+ treatment and cell oxidation in adult ventricular myocytes [ 267 ].…”

Molecular Pathogenesis of Cardiac Arrhythmia

“…In other words, cardiac mitochondrial function is being addressed as a systemic challenge. In this Special Issue, Dr. Takeuchi and Prof. Matsuoka provide a review focusing on Ca 2+ dynamics in cardiac mitochondria [ 2 ]. Mitochondrial biophysical variables inside the cell are indirectly measured by selective drugs, selective fluorescent reagents, and selective genetic modification.…”