The electroneutral exchange of protons for Na+ and K+ across the mitochondrial inner membrane contributes to organellar volume and Ca2+homeostasis. The molecular nature of these transporters remains unknown. In this report, we characterize a novel gene (YDR456w; renamed NHA2) in Saccharomyces cerevisiae whose deduced protein sequence is homologous to members of the mammalian Na+/H+ exchanger gene family. Fluorescence microscopy showed that a Nha2-green fluorescent protein chimera colocalizes with 4′,6-diamidino-2-phenylindole staining of mitochondrial DNA. To assess the function of Nha2, we deleted the NHA2 gene by homologous disruption and found that benzamil-inhibitable, acid-activated 22Na+ uptake into mitochondria was abolished in the mutant strain. It also showed retarded growth on nonfermentable carbon sources and severely reduced survival during the stationary phase of the cell cycle compared with the parental strain, consistent with a defect in aerobic metabolism. Sequence comparisons revealed that Nha2 has highest identity to a putative Na+/H+ exchanger homologue (KIAA0267; renamed NHE6) in humans. Northern blot analysis demonstrated that NHE6 is ubiquitously expressed but is most abundant in mitochondrion-rich tissues such as brain, skeletal muscle, and heart. Fluorescence microscopy showed that a NHE6-green fluorescent protein chimera also accumulates in mitochondria of transfected HeLa cells. These data indicate that NHA2 and NHE6 encode homologous Na+/H+ exchangers and suggest they may be important for mitochondrial function in lower and higher eukaryotes, respectively. The electroneutral exchange of protons for Na+ and K+ across the mitochondrial inner membrane contributes to organellar volume and Ca2+homeostasis. The molecular nature of these transporters remains unknown. In this report, we characterize a novel gene (YDR456w; renamed NHA2) in Saccharomyces cerevisiae whose deduced protein sequence is homologous to members of the mammalian Na+/H+ exchanger gene family. Fluorescence microscopy showed that a Nha2-green fluorescent protein chimera colocalizes with 4′,6-diamidino-2-phenylindole staining of mitochondrial DNA. To assess the function of Nha2, we deleted the NHA2 gene by homologous disruption and found that benzamil-inhibitable, acid-activated 22Na+ uptake into mitochondria was abolished in the mutant strain. It also showed retarded growth on nonfermentable carbon sources and severely reduced survival during the stationary phase of the cell cycle compared with the parental strain, consistent with a defect in aerobic metabolism. Sequence comparisons revealed that Nha2 has highest identity to a putative Na+/H+ exchanger homologue (KIAA0267; renamed NHE6) in humans. Northern blot analysis demonstrated that NHE6 is ubiquitously expressed but is most abundant in mitochondrion-rich tissues such as brain, skeletal muscle, and heart. Fluorescence microscopy showed that a NHE6-green fluorescent protein chimera also accumulates in mitochondria of transfected HeLa cells. These data indicate that NHA2 and NHE6 encode homologous Na+/H+ exchangers and suggest they may be important for mitochondrial function in lower and higher eukaryotes, respectively. Electroneutral monovalent cation/proton antiporters or exchangers are important components of mitochondrial volume and Ca2+homeostasis. In mammals, the latter is achieved by an integrated cycle of distinct Ca2+ uniport and Na+/H+and Na+/Ca2+ antiport pathways located in the inner membrane (1Mitchell P. Moyle J. Eur. J. Biochem. 1969; 9: 149-155Crossref PubMed Scopus (257) Google Scholar, 2Crompton M. Heid I. Eur. J. Biochem. 1978; 91: 599-608Crossref PubMed Scopus (116) Google Scholar, 3Crompton M. Moser R. 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One of these preferentially mediates the exchange of matrix Na+for intermembrane H+ generated by respiration (i.e. a Na+-selective Na+/H+ exchanger (NHE) 1The abbreviations used are: NHE, Na+/H+ exchanger; PCR, polymerase chain reaction; 5′-RACE, 5′-rapid amplification of cDNA end; DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride; GFP, green fluorescent protein; TES, 2-{[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino} ethanesulfonic acid. 1The abbreviations used are: NHE, Na+/H+ exchanger; PCR, polymerase chain reaction; 5′-RACE, 5′-rapid amplification of cDNA end; DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride; GFP, green fluorescent protein; TES, 2-{[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino} ethanesulfonic acid.) (1Mitchell P. Moyle J. Eur. J. Biochem. 1969; 9: 149-155Crossref PubMed Scopus (257) Google Scholar, 13Garlid K.D. Shariat-Madar Z. Nath S. Jezek P. J. Biol. Chem. 1991; 266: 6518-6523Abstract Full Text PDF PubMed Google Scholar). This mechanism also transports Li+ (and possibly NH4+) at a much lower rate and is inhibited by benzamil derivatives of amiloride (14Nath S. Garlid K.D. Lemasters J.J. Hackenbrock C.R. Thurman R.G. Westerhoff H.V. Integration of Mitochondrial Function. Plenum Publishing Corp., New York1988: 357-364Crossref Google Scholar, 15Kapus A. Lukacs G.L. Cragoe Jr., E.J. Ligeti E. Fonyó A. Biochim. Biophys. Acta. 1988; 944: 383-390Crossref PubMed Scopus (32) Google Scholar, 16Brierley G.P. Davis M.H. Cragoe Jr., E.J. Jung D.W. Biochemistry. 1989; 28: 4337-4354Crossref Scopus (26) Google Scholar, 17Sastrasinh M. Young P. Cragoe Jr., E.J. Sastrasinh S. Am. J. Physiol. 1995; 268: C1227-C1234Crossref PubMed Google Scholar). It is constitutively active in respiring mitochondria and is primarily responsible for establishing the [Na+] gradient ([Na+] i < [Na+] o) that allows Na+-dependent extrusion of matrix Ca2+ (18Jung D.W. Apel L.M. Brierley G.P. Am. J. Physiol. 1992; 262: C1047-C1055Crossref PubMed Google Scholar). The other monovalent cation/H+exchanger is latent, transports all alkali cations (i.e.Li+, Na+, K+, Rb+, and Cs+) at similar rates, and is antagonized by quinine, dicyclohexylcarbodiimide, and propranolol (19Garlid K.D. Biochem. Biophys. Res. Commun. 1978; 83: 1450-1455Crossref PubMed Scopus (31) Google Scholar, 20Martin W.H. Beavis A.D. Garlid K.D. J. Biol. Chem. 1984; 259: 2062-2065Abstract Full Text PDF PubMed Google Scholar, 21Brierley G.P. Jurkowitz M.S. Farooqui T. Jung D.W. J. Biol. Chem. 1984; 259: 14672-14678Abstract Full Text PDF PubMed Google Scholar). Since K+ is the predominant intracellular alkali cation, it is usually referred to as a K+/H+ exchanger. In isolated mitochondria, it is active only upon depletion of matrix Mg2+ and simultaneous elevation of matrix pH or upon hypotonic swelling (19Garlid K.D. Biochem. Biophys. Res. 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The of in the is for the of the NHA2 this was not in the The gene was by the of the of by of the at the of the of NHA2 by of the of the The was into the by the 1995; PubMed Scopus Google Scholar) and on by the and of the of the of NHA2 was by analysis of to an of the NHA2 and an sequence of The to the of S. cerevisiae but the was with and and into the in the by M. PubMed Scopus Google Scholar). This in an the of the To a an was by at the of the NHE6 the the NHE6 sequence was in with the of cDNA a A. E. 1997; Scopus Google Scholar), and into the mammalian The and into and on with and into of and to and to levels of the respectively. To mitochondria in in 4′,6-diamidino-2-phenylindole for at by by for in these mitochondrial is preferentially compared with M. P. Methods Enzymol. 1991; PubMed Scopus Google Scholar). The by microscopy with the for for HeLa transfected with the by the H. Cell. Biol. PubMed Scopus Google Scholar). for at and at a reduced for to the of GFP, as H. S. K. K. S. 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Integration of Mitochondrial Function. Plenum Publishing Corp., New York1988: 357-364Crossref Google Scholar, 15Kapus A. Lukacs G.L. Cragoe Jr., E.J. Ligeti E. Fonyó A. Biochim. Biophys. Acta. 1988; 944: 383-390Crossref PubMed Scopus (32) Google Scholar, 16Brierley G.P. Davis M.H. Cragoe Jr., E.J. Jung D.W. Biochemistry. 1989; 28: 4337-4354Crossref Scopus (26) Google Scholar, 17Sastrasinh M. Young P. Cragoe Jr., E.J. Sastrasinh S. Am. J. Physiol. 1995; 268: C1227-C1234Crossref PubMed Google Scholar) compared with membrane J. J. Biol. Chem. 268: Full Text PDF PubMed Google Scholar, J. J. Biol. Chem. 268: Full Text PDF PubMed Google Scholar). 22Na+ was also inhibited by Li+ antagonized Na+ not 22Na+ was in the mitochondria. These data the that Nha2 is a Na+/H+ exchanger in mitochondria. To assess the of the NHA2 gene on mitochondrial the and mutant to growth that primarily on aerobic for energy Methods Enzymol. 1991; PubMed Scopus Google Scholar, M. E. Rev. PubMed Google Scholar). 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