Molecular identity and functional properties of the mitochondrial Na+/Ca2+ exchanger

Abstract

The mitochondrial membrane potential that powers the generation of ATP also facilitates mitochondrial Ca(2+) shuttling. This process is fundamental to a wide range of cellular activities, as it regulates ATP production, shapes cytosolic and endoplasmic recticulum Ca(2+) signaling, and determines cell fate. Mitochondrial Ca(2+) transport is mediated primarily by two major transporters: a Ca(2+) uniporter that mediates Ca(2+) uptake and a Na(+)/Ca(2+) exchanger that subsequently extrudes mitochondrial Ca(2+). In this minireview, we focus on the specific role of the mitochondrial Na(+)/Ca(2+) exchanger and describe its ion exchange mechanism, regulation by ions, and putative partner proteins. We discuss the recent molecular identification of the mitochondrial exchanger and how its activity is linked to physiological and pathophysiological processes.

FIGURE 1.

Functional and molecular identification of the mitochondrial NCX. a, the first evidence for Na⁺- or Li⁺-dependent mitochondrial Ca²⁺ exchange. Original data were taken from Ref. . Li⁺ (▴), Na⁺ (○), or K⁺ (●) was added to isolated mitochondria while monitoring Ca²⁺ efflux. b and c, note that Na⁺ promoted the mitochondrial efflux of Ca²⁺, demonstrating a Na⁺/Ca²⁺ exchange pathway in this organelle. Unlike the plasma membrane NCX family members, the mitochondrial exchanger also mediated Li⁺/Ca²⁺ exchange, indicating that it has distinct functional properties. NCLX was identified as the mitochondrial exchanger. Studies were conducted on cells expressing the mitochondrial Ca²⁺ sensor mito-pericam. Knocking down the expression of mitochondrial NCLX using NCLX siRNA (si NCLX) abolished either Na⁺-dependent (b) or Li⁺-dependent (c) mitochondrial Ca²⁺ efflux. Thus, NCLX shares similar functional properties with the mitochondrial NCX. Original data were taken from Ref. . si control, control siRNA.

FIGURE 2.

Schematic representation of ions, transporters, and kinases that interact or modulate the activity of the mitochondrial NCX. Functional cross-talk between the ER and plasma membrane fluxes of Na⁺ and Ca²⁺ regulates the activity of the mitochondrial NCX, which in turn controls the Ca²⁺ content in the ER or plasma membrane microdomain and Ca²⁺ signaling in the cytosol. NHE, Na⁺/H⁺ exchanger; RyR, ryanodine receptor; IP₃R, inositol trisphosphate receptor; SOC, store-operated calcium channel; LTCC, L-type Ca²⁺ channel; TRP, transient receptor potential channel.