Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 29, Pages 20377-20385Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.540898
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Funding
- Swiss National Foundation [310030B_133126]
- Swiss National Science Foundation (SNF) [310030B_133126] Funding Source: Swiss National Science Foundation (SNF)
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Mitochondria capture and subsequently release Ca2+ ions, thereby sensing and shaping cellular Ca2+ signals. The Ca2+ uniporter MCU mediates Ca2+ uptake, whereas NCLX (mitochondrial Na/Ca exchanger) and LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) were proposed to exchange Ca2+ against Na+ or H+, respectively. Here we study the role of these ion exchangers in mitochondrial Ca2+ extrusion and in Ca2+-metabolic coupling. Both NCLX and LETM1 proteins were expressed in HeLa cells mitochondria. The rate of mitochondrial Ca2+ efflux, measured with a genetically encoded indicator during agonist stimulations, increased with the amplitude of mitochondrial Ca2+ ([Ca2+](mt)) elevations. NCLX overexpression enhanced the rates of Ca2+ efflux, whereas increasing LETM1 levels had no impact on Ca2+ extrusion. The fluorescence of the redox-sensitive probe roGFP increased during [Ca2+](mt) elevations, indicating a net reduction of the matrix. This redox response was abolished by NCLX overexpression and restored by the Na+/Ca2+ exchanger inhibitor CGP37157. The [Ca2+](mt) elevations were associated with increases in the autofluorescence of NAD(P)H, whose amplitude was strongly reduced by NCLX overexpression, an effect reverted by Na+/Ca2+ exchange inhibition. We conclude that NCLX, but not LETM1, mediates Ca2+ extrusion from mitochondria. By controlling the duration of matrix Ca2+ elevations, NCLX contributes to the regulation of NAD(P)H production and to the conversion of Ca2+ signals into redox changes.
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