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• W2074179637 abstract "The biogenesis of mitochondria requires the import of a large number of proteins from the cytosol [1Dolezal P. Likic V. Tachezy J. Lithgow T. Evolution of the molecular machines for protein import into mitochondria.Science. 2006; 313: 314-318Crossref PubMed Scopus (416) Google Scholar, 2Neupert W. Herrmann J.M. Translocation of proteins into mitochondria.Annu. Rev. Biochem. 2007; 76: 723-749Crossref PubMed Scopus (1025) Google Scholar]. Although numerous studies have defined the proteinaceous machineries that mediate mitochondrial protein sorting, little is known about the role of lipids in mitochondrial protein import. Cardiolipin, the signature phospholipid of the mitochondrial inner membrane [3Daum G. Vance J.E. Import of lipids into mitochondria.Prog. Lipid Res. 1997; 36: 103-130Crossref PubMed Scopus (198) Google Scholar, 4Mileykovskaya E. Zhang M. Dowhan W. Cardiolipin in energy transducing membranes.Biochemistry (Mosc.). 2005; 70: 154-158Crossref PubMed Scopus (74) Google Scholar, 5Joshi A.S. Zhou J. Gohil V.M. Chen S. Greenberg M.L. Cellular functions of cardiolipin in yeast.Biochim. Biophys. Acta. 2009; 1793: 212-218Crossref PubMed Scopus (111) Google Scholar], affects the stability of many inner-membrane protein complexes [6Jiang F. Ryan M.T. Schlame M. Zhao M. Gu Z. Klingenberg M. Pfanner N. Greenberg M.L. Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function.J. Biol. Chem. 2000; 275: 22387-22394Crossref PubMed Scopus (305) Google Scholar, 7Pfeiffer K. Gohil V. Stuart R.A. Hunte C. Brandt U. Greenberg M.L. Schägger H. Cardiolipin stabilizes respiratory chain supercomplexes.J. Biol. Chem. 2003; 278: 52873-52880Crossref PubMed Scopus (572) Google Scholar, 8Nury H. Dahout-Gonzalez C. Trezeguet V. Lauquin G. Brandolin G. Pebay-Peyroula E. Structural basis for lipid-mediated interactions between mitochondrial ADP/ATP carrier monomers.FEBS Lett. 2005; 579: 6031-6036Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 9Zhang M. Mileykovskaya E. Dowhan W. Cardiolipin is essential for organization of complexes III and IV into a supercomplex in intact yeast mitochondria.J. Biol. Chem. 2005; 280: 29403-29408Crossref PubMed Scopus (250) Google Scholar, 10Claypool S.M. Oktay Y. Boontheung P. Loo J.A. Koehler C.M. Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane.J. Cell Biol. 2008; 182: 937-950Crossref PubMed Scopus (218) Google Scholar, 11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar, 12Wenz T. Hielscher R. Hellwig P. Schägger H. Richers S. Hunte C. Role of phospholipids in respiratory cytochrome bc1 complex catalysis and supercomplex formation.Biochim. Biophys. Acta. 2009; 1787: 609-616Crossref PubMed Scopus (124) Google Scholar]. Perturbation of cardiolipin metabolism leads to the X-linked cardioskeletal myopathy Barth syndrome [13Bione S. D'Adamo P. Maestrini E. Gedeon A.K. Bolhuis P.A. Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome.Nat. Genet. 1996; 12: 385-389Crossref PubMed Scopus (560) Google Scholar, 14Barth P.G. Valianpour F. Bowen V.M. Lam J. Duran M. Vaz F.M. Wanders R.J. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): An update.Am. J. Med. Genet. A. 2004; 126A: 349-354Crossref PubMed Scopus (216) Google Scholar, 15Brandner K. Mick D.U. Frazier A.E. Taylor R.D. Meisinger C. Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: Implications for Barth syndrome.Mol. Biol. Cell. 2005; 16: 5202-5214Crossref PubMed Scopus (160) Google Scholar, 16McKenzie M. Lazarou M. Thorburn D.R. Ryan M.T. Mitochondrial respiratory chain supercomplexes are destabilized in Barth syndrome patients.J. Mol. Biol. 2006; 361: 462-469Crossref PubMed Scopus (290) Google Scholar, 17Schlame M. Ren M. Barth syndrome, a human disorder of cardiolipin metabolism.FEBS Lett. 2006; 580: 5450-5455Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 18Claypool S.M. Boontheung P. McCaffery J.M. Loo J.A. Koehler C.M. The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome.Mol. Biol. Cell. 2008; 19: 5143-5155Crossref PubMed Scopus (81) Google Scholar]. We report that cardiolipin affects the preprotein translocases of the mitochondrial outer membrane. Cardiolipin mutants genetically interact with mutants of outer-membrane translocases. Mitochondria from cardiolipin yeast mutants, as well as Barth syndrome patients, are impaired in the biogenesis of outer-membrane proteins. Our findings reveal a new role for cardiolipin in protein sorting at the mitochondrial outer membrane and bear implications for the pathogenesis of Barth syndrome. The biogenesis of mitochondria requires the import of a large number of proteins from the cytosol [1Dolezal P. Likic V. Tachezy J. Lithgow T. Evolution of the molecular machines for protein import into mitochondria.Science. 2006; 313: 314-318Crossref PubMed Scopus (416) Google Scholar, 2Neupert W. Herrmann J.M. Translocation of proteins into mitochondria.Annu. Rev. Biochem. 2007; 76: 723-749Crossref PubMed Scopus (1025) Google Scholar]. Although numerous studies have defined the proteinaceous machineries that mediate mitochondrial protein sorting, little is known about the role of lipids in mitochondrial protein import. Cardiolipin, the signature phospholipid of the mitochondrial inner membrane [3Daum G. Vance J.E. Import of lipids into mitochondria.Prog. Lipid Res. 1997; 36: 103-130Crossref PubMed Scopus (198) Google Scholar, 4Mileykovskaya E. Zhang M. Dowhan W. Cardiolipin in energy transducing membranes.Biochemistry (Mosc.). 2005; 70: 154-158Crossref PubMed Scopus (74) Google Scholar, 5Joshi A.S. Zhou J. Gohil V.M. Chen S. Greenberg M.L. Cellular functions of cardiolipin in yeast.Biochim. Biophys. Acta. 2009; 1793: 212-218Crossref PubMed Scopus (111) Google Scholar], affects the stability of many inner-membrane protein complexes [6Jiang F. Ryan M.T. Schlame M. Zhao M. Gu Z. Klingenberg M. Pfanner N. Greenberg M.L. Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function.J. Biol. Chem. 2000; 275: 22387-22394Crossref PubMed Scopus (305) Google Scholar, 7Pfeiffer K. Gohil V. Stuart R.A. Hunte C. Brandt U. Greenberg M.L. Schägger H. Cardiolipin stabilizes respiratory chain supercomplexes.J. Biol. Chem. 2003; 278: 52873-52880Crossref PubMed Scopus (572) Google Scholar, 8Nury H. Dahout-Gonzalez C. Trezeguet V. Lauquin G. Brandolin G. Pebay-Peyroula E. Structural basis for lipid-mediated interactions between mitochondrial ADP/ATP carrier monomers.FEBS Lett. 2005; 579: 6031-6036Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 9Zhang M. Mileykovskaya E. Dowhan W. Cardiolipin is essential for organization of complexes III and IV into a supercomplex in intact yeast mitochondria.J. Biol. Chem. 2005; 280: 29403-29408Crossref PubMed Scopus (250) Google Scholar, 10Claypool S.M. Oktay Y. Boontheung P. Loo J.A. Koehler C.M. Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane.J. Cell Biol. 2008; 182: 937-950Crossref PubMed Scopus (218) Google Scholar, 11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar, 12Wenz T. Hielscher R. Hellwig P. Schägger H. Richers S. Hunte C. Role of phospholipids in respiratory cytochrome bc1 complex catalysis and supercomplex formation.Biochim. Biophys. Acta. 2009; 1787: 609-616Crossref PubMed Scopus (124) Google Scholar]. Perturbation of cardiolipin metabolism leads to the X-linked cardioskeletal myopathy Barth syndrome [13Bione S. D'Adamo P. Maestrini E. Gedeon A.K. Bolhuis P.A. Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome.Nat. Genet. 1996; 12: 385-389Crossref PubMed Scopus (560) Google Scholar, 14Barth P.G. Valianpour F. Bowen V.M. Lam J. Duran M. Vaz F.M. Wanders R.J. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): An update.Am. J. Med. Genet. A. 2004; 126A: 349-354Crossref PubMed Scopus (216) Google Scholar, 15Brandner K. Mick D.U. Frazier A.E. Taylor R.D. Meisinger C. Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: Implications for Barth syndrome.Mol. Biol. Cell. 2005; 16: 5202-5214Crossref PubMed Scopus (160) Google Scholar, 16McKenzie M. Lazarou M. Thorburn D.R. Ryan M.T. Mitochondrial respiratory chain supercomplexes are destabilized in Barth syndrome patients.J. Mol. Biol. 2006; 361: 462-469Crossref PubMed Scopus (290) Google Scholar, 17Schlame M. Ren M. Barth syndrome, a human disorder of cardiolipin metabolism.FEBS Lett. 2006; 580: 5450-5455Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 18Claypool S.M. Boontheung P. McCaffery J.M. Loo J.A. Koehler C.M. The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome.Mol. Biol. Cell. 2008; 19: 5143-5155Crossref PubMed Scopus (81) Google Scholar]. We report that cardiolipin affects the preprotein translocases of the mitochondrial outer membrane. Cardiolipin mutants genetically interact with mutants of outer-membrane translocases. Mitochondria from cardiolipin yeast mutants, as well as Barth syndrome patients, are impaired in the biogenesis of outer-membrane proteins. Our findings reveal a new role for cardiolipin in protein sorting at the mitochondrial outer membrane and bear implications for the pathogenesis of Barth syndrome. Mitochondria play crucial roles in cellular bioenergetics, programmed cell death, and the metabolism of amino acids, lipids, heme, and iron [1Dolezal P. Likic V. Tachezy J. Lithgow T. Evolution of the molecular machines for protein import into mitochondria.Science. 2006; 313: 314-318Crossref PubMed Scopus (416) Google Scholar, 2Neupert W. Herrmann J.M. Translocation of proteins into mitochondria.Annu. Rev. Biochem. 2007; 76: 723-749Crossref PubMed Scopus (1025) Google Scholar, 19Lill R. Mühlenhoff U. Maturation of iron-sulfur proteins in eukaryotes: Mechanisms, connected processes, and diseases.Annu. Rev. Biochem. 2008; 77: 669-700Crossref PubMed Scopus (466) Google Scholar]. To fulfill these tasks, mitochondria contain ∼1000 different proteins, 99% of which have to be imported from the cytosol [1Dolezal P. Likic V. Tachezy J. Lithgow T. Evolution of the molecular machines for protein import into mitochondria.Science. 2006; 313: 314-318Crossref PubMed Scopus (416) Google Scholar, 2Neupert W. Herrmann J.M. Translocation of proteins into mitochondria.Annu. Rev. Biochem. 2007; 76: 723-749Crossref PubMed Scopus (1025) Google Scholar]. Of the mitochondrial lipids, the dimeric phospholipid cardiolipin is characteristic for this organelle [3Daum G. Vance J.E. Import of lipids into mitochondria.Prog. Lipid Res. 1997; 36: 103-130Crossref PubMed Scopus (198) Google Scholar, 4Mileykovskaya E. Zhang M. Dowhan W. Cardiolipin in energy transducing membranes.Biochemistry (Mosc.). 2005; 70: 154-158Crossref PubMed Scopus (74) Google Scholar, 5Joshi A.S. Zhou J. Gohil V.M. Chen S. Greenberg M.L. Cellular functions of cardiolipin in yeast.Biochim. Biophys. Acta. 2009; 1793: 212-218Crossref PubMed Scopus (111) Google Scholar]. Cardiolipin is synthesized in the inner membrane and affects the stability of various inner-membrane protein complexes, including respiratory chain complexes and metabolite carriers [6Jiang F. Ryan M.T. Schlame M. Zhao M. Gu Z. Klingenberg M. Pfanner N. Greenberg M.L. Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function.J. Biol. Chem. 2000; 275: 22387-22394Crossref PubMed Scopus (305) Google Scholar, 7Pfeiffer K. Gohil V. Stuart R.A. Hunte C. Brandt U. Greenberg M.L. Schägger H. Cardiolipin stabilizes respiratory chain supercomplexes.J. Biol. Chem. 2003; 278: 52873-52880Crossref PubMed Scopus (572) Google Scholar, 8Nury H. Dahout-Gonzalez C. Trezeguet V. Lauquin G. Brandolin G. Pebay-Peyroula E. Structural basis for lipid-mediated interactions between mitochondrial ADP/ATP carrier monomers.FEBS Lett. 2005; 579: 6031-6036Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 9Zhang M. Mileykovskaya E. Dowhan W. Cardiolipin is essential for organization of complexes III and IV into a supercomplex in intact yeast mitochondria.J. Biol. Chem. 2005; 280: 29403-29408Crossref PubMed Scopus (250) Google Scholar, 10Claypool S.M. Oktay Y. Boontheung P. Loo J.A. Koehler C.M. Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane.J. Cell Biol. 2008; 182: 937-950Crossref PubMed Scopus (218) Google Scholar, 11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar, 12Wenz T. Hielscher R. Hellwig P. Schägger H. Richers S. Hunte C. Role of phospholipids in respiratory cytochrome bc1 complex catalysis and supercomplex formation.Biochim. Biophys. Acta. 2009; 1787: 609-616Crossref PubMed Scopus (124) Google Scholar]. Mitochondria from mutants defective in cardiolipin biosynthesis have a reduced inner-membrane potential Δψ, leading to a reduction of the Δψ-dependent protein translocation into the inner membrane [6Jiang F. Ryan M.T. Schlame M. Zhao M. Gu Z. Klingenberg M. Pfanner N. Greenberg M.L. Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function.J. Biol. Chem. 2000; 275: 22387-22394Crossref PubMed Scopus (305) Google Scholar, 11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar, 15Brandner K. Mick D.U. Frazier A.E. Taylor R.D. Meisinger C. Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: Implications for Barth syndrome.Mol. Biol. Cell. 2005; 16: 5202-5214Crossref PubMed Scopus (160) Google Scholar, 20Xu Y. Sutachan J.J. Plesken H. Kelley R.I. Schlame M. Characterization of lymphoblast mitochondria from patients with Barth syndrome.Lab. Invest. 2005; 85: 823-830Crossref PubMed Scopus (103) Google Scholar]. Mutations of the phospholipid transacylase tafazzin, which remodels the fatty acyl side chains of cardiolipin, cause the severe human disease Barth syndrome [13Bione S. D'Adamo P. Maestrini E. Gedeon A.K. Bolhuis P.A. Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome.Nat. Genet. 1996; 12: 385-389Crossref PubMed Scopus (560) Google Scholar, 14Barth P.G. Valianpour F. Bowen V.M. Lam J. Duran M. Vaz F.M. Wanders R.J. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): An update.Am. J. Med. Genet. A. 2004; 126A: 349-354Crossref PubMed Scopus (216) Google Scholar, 17Schlame M. Ren M. Barth syndrome, a human disorder of cardiolipin metabolism.FEBS Lett. 2006; 580: 5450-5455Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]. The mitochondrial defects of tafazzin mutants have been attributed to defects of inner-membrane protein complexes [15Brandner K. Mick D.U. Frazier A.E. Taylor R.D. Meisinger C. Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: Implications for Barth syndrome.Mol. Biol. Cell. 2005; 16: 5202-5214Crossref PubMed Scopus (160) Google Scholar, 16McKenzie M. Lazarou M. Thorburn D.R. Ryan M.T. Mitochondrial respiratory chain supercomplexes are destabilized in Barth syndrome patients.J. Mol. Biol. 2006; 361: 462-469Crossref PubMed Scopus (290) Google Scholar, 17Schlame M. Ren M. Barth syndrome, a human disorder of cardiolipin metabolism.FEBS Lett. 2006; 580: 5450-5455Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 18Claypool S.M. Boontheung P. McCaffery J.M. Loo J.A. Koehler C.M. The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome.Mol. Biol. Cell. 2008; 19: 5143-5155Crossref PubMed Scopus (81) Google Scholar]. Interestingly, tafazzin was not only found in the inner membrane, but also in the outer membrane [15Brandner K. Mick D.U. Frazier A.E. Taylor R.D. Meisinger C. Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: Implications for Barth syndrome.Mol. Biol. Cell. 2005; 16: 5202-5214Crossref PubMed Scopus (160) Google Scholar, 21Claypool S.M. McCaffery J.M. Koehler C.M. Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins.J. Cell Biol. 2006; 174: 379-390Crossref PubMed Scopus (106) Google Scholar]. However, different views have been reported on the presence of cardiolipin in the outer membrane [3Daum G. Vance J.E. Import of lipids into mitochondria.Prog. Lipid Res. 1997; 36: 103-130Crossref PubMed Scopus (198) Google Scholar, 22de Kroon A.I. Dolis D. Mayer A. Lill R. de Kruijff B. Phospholipid composition of highly purified mitochondrial outer membranes of rat liver and Neurospora crassa: Is cardiolipin present in the mitochondrial outer membrane?.Biochim. Biophys. Acta. 1997; 1325: 108-116Crossref PubMed Scopus (187) Google Scholar, 23Kim T.H. Zhao Y. Ding W.X. Shin J.N. He X. Seo Y.W. Chen J. Rabinowich H. Amoscato A.A. Yin X.M. Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome c release.Mol. Biol. Cell. 2004; 15: 3061-3072Crossref PubMed Scopus (146) Google Scholar, 24Schafer B. Quispe J. Choudhary V. Chipuk J.E. Ajero T.G. Du H. Schneiter R. Kuwana T. Mitochondrial outer membrane proteins assist Bid in Bax-mediated lipidic pore formation.Mol. Biol. Cell. 2009; 20: 2276-2285Crossref PubMed Scopus (95) Google Scholar], and little has been known on a possible function of outer-membrane cardiolipin, the only exception being a controversial discussion on the role of cardiolipin in outer-membrane permeabilization in apoptosis [23Kim T.H. Zhao Y. Ding W.X. Shin J.N. He X. Seo Y.W. Chen J. Rabinowich H. Amoscato A.A. Yin X.M. Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome c release.Mol. Biol. Cell. 2004; 15: 3061-3072Crossref PubMed Scopus (146) Google Scholar, 24Schafer B. Quispe J. Choudhary V. Chipuk J.E. Ajero T.G. Du H. Schneiter R. Kuwana T. Mitochondrial outer membrane proteins assist Bid in Bax-mediated lipidic pore formation.Mol. Biol. Cell. 2009; 20: 2276-2285Crossref PubMed Scopus (95) Google Scholar, 25Kuwana T. Mackey M.R. Perkins G. Ellisman M.H. Latterich M. Schneter R. Green D.R. Newmeyer D.D. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane.Cell. 2002; 111: 331-342Abstract Full Text Full Text PDF PubMed Scopus (1170) Google Scholar, 26Gonzalvez F. Schug Z.T. Houtkooper R.H. MacKenzie E.D. Brooks D.G. Wanders R.S. Petit P.X. Vaz F.M. Gottlieb E. Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.J. Cell Biol. 2008; 183: 681-696Crossref PubMed Scopus (209) Google Scholar]. Because apoptotic defects have not been found in Barth syndrome [26Gonzalvez F. Schug Z.T. Houtkooper R.H. MacKenzie E.D. Brooks D.G. Wanders R.S. Petit P.X. Vaz F.M. Gottlieb E. Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.J. Cell Biol. 2008; 183: 681-696Crossref PubMed Scopus (209) Google Scholar], experimental evidence for a functional relation of Barth syndrome and the outer mitochondrial membrane has been lacking. To determine the presence of cardiolipin in the outer membrane of Saccharomyces cerevisiae mitochondria, we prepared highly pure outer-membrane vesicles from isolated yeast mitochondria. The liquid chromatography/mass spectrometry profile demonstrated the presence of cardiolipin in the outer membrane (Figure 1A, top; total mitochondrial membranes are shown for comparison, bottom). A quantitative determination revealed that the concentration of cardiolipin in the outer membrane was 25% of the cardiolipin concentration of total mitochondrial membranes (Figure 1B). To determine the purity of the outer-membrane preparation, we performed a western blot titration from 100% to 1%, demonstrating that a contamination with inner-membrane marker proteins (Cox1, Sdh4) was below the detection limit and thus far below 1% (Figure 1B). In contrast, a fraction of tafazzin (Taz1) was clearly present in the purified outer membranes. With an antiserum against the authentic (untagged) protein, we found Taz1 at a 16% level in the outer membrane (Figure 1B). To study a possible role of cardiolipin in the outer membrane, we used yeast mutants that lacked either cardiolipin synthase (crd1Δ) or tafazzin (taz1Δ). crd1Δ cells lack cardiolipin, whereas in taz1Δ cells, the cardiolipin levels are lower and immature cardiolipin species (lacking unsaturated fatty acids) and monolysocardiolipin are observed [4Mileykovskaya E. Zhang M. Dowhan W. Cardiolipin in energy transducing membranes.Biochemistry (Mosc.). 2005; 70: 154-158Crossref PubMed Scopus (74) Google Scholar, 5Joshi A.S. Zhou J. Gohil V.M. Chen S. Greenberg M.L. Cellular functions of cardiolipin in yeast.Biochim. Biophys. Acta. 2009; 1793: 212-218Crossref PubMed Scopus (111) Google Scholar, 17Schlame M. Ren M. Barth syndrome, a human disorder of cardiolipin metabolism.FEBS Lett. 2006; 580: 5450-5455Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]. We generated double-deletion mutants with genes encoding components of the two protein transport machineries of the outer membrane: the translocase of the outer membrane (TOM complex) and the sorting and assembly machinery (SAM complex). The majority of tom/sam deletion mutants showed synthetic growth defects with the cardiolipin mutants, including a synthetic lethality of tom5Δ crd1Δ and tom5Δ taz1Δ (Figures 1C and 1D). These results indicate a genetic interaction of cardiolipin mutants with components of outer-membrane protein import. To define the molecular steps affected in protein import, we analyzed the translocases and import capability of isolated mitochondria. Because cardiolipin mutants are temperature sensitive for growth [6Jiang F. Ryan M.T. Schlame M. Zhao M. Gu Z. Klingenberg M. Pfanner N. Greenberg M.L. Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function.J. Biol. Chem. 2000; 275: 22387-22394Crossref PubMed Scopus (305) Google Scholar, 11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar], we searched for conditions that minimized indirect, pleiotropic effects. We found that growth of the cells at very low temperature (21°C) yielded crd1Δ and taz1Δ mitochondria that contained the components of the protein-import machineries of outer and inner membranes in amounts close to that of wild-type mitochondria (Figure 2A). Thus, alterations of steady-state protein levels, which would indirectly affect mitochondrial biogenesis and function, were minimized (facilitating the identification of primary mutant defects by a kinetic analysis of protein import, as outlined below). The isolated mutant mitochondria contained an intact outer membrane because the intermembrane space-exposed Tim23 subunit of the translocase of the inner membrane was protected against externally added Proteinase K (unless the outer membrane was disrupted by swelling) (see Figure S1A available online). To analyze the TOM complex, we lysed mitochondria with digitonin and separated the protein complexes by blue native electrophoresis. The mobility of the TOM complex was altered in crd1Δ and tam41Δ mitochondria that lack cardiolipin (Figure 2B) (Tam41 is required for an early step of cardiolipin biosynthesis [11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar]). For comparison, the mobility of the inner-membrane TIM22 complex, but not of the Tim9-Tim10 complex of the intermembrane space, was also altered in crd1Δ mitochondria as reported (Figure S1B) [11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar]. In taz1Δ mitochondria, the mobility of the TOM complex and the TIM22 complex was close to that of wild-type mitochondria (Figures 2B; Figure S1B). These results indicated that the lack of cardiolipin affected the organization of the TOM complex. We thus performed a 2D electrophoresis (blue native electrophoresis followed by SDS polyacrylamide gel electrophoresis [SDS-PAGE]) to determine whether the lack of cardiolipin influenced the association of Tom subunits. The core components Tom40, Tom22, and the small Tom subunits were present in the TOM complex independently of the presence or absence of cardiolipin (Figure 2C). However, the association of the receptor Tom20 with the TOM complex was clearly impaired (Figure 2C). Tom20 is more loosely associated with the TOM complex, and thus only a fraction of this receptor migrated with the TOM complex under wild-type conditions. In crd1Δ mitochondria, this fraction was considerably reduced (Figure 2C), indicating that cardiolipin influences the interaction of Tom20 with the TOM complex. To monitor protein import, we synthesized and radiolabeled the precursor proteins in a cell-free system and incubated them with isolated mitochondria. The Δψ-dependent import of hydrophilic precursor proteins across the inner membrane (F1β, Su9-DHFR) was not affected or was only mildly affected in mitochondria lacking Crd1 or Taz1 (Figure S2A), in agreement with the observation that cardiolipin-deficient cells grown at low temperature are able to generate a Δψ [11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar]. (It has been shown that at higher temperature, cardiolipin-deficient mitochondria are partially impaired in protein import across the inner membrane, concomitant with a decrease of Δψ [6Jiang F. Ryan M.T. Schlame M. Zhao M. Gu Z. Klingenberg M. Pfanner N. Greenberg M.L. Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function.J. Biol. Chem. 2000; 275: 22387-22394Crossref PubMed Scopus (305) Google Scholar, 11Kutik S. Rissler M. Guan X.L. Guiard B. Shui G. Gebert N. Heacock P.N. Rehling P. Dowhan W. Wenk M.R. et al.The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis.J. Cell Biol. 2008; 183: 1213-1221Crossref PubMed Scopus (96) Google Scholar].) However, import of the multispanning inner-membrane protein Oxa1 was of lower efficiency in crd1Δ mitochondria compared to wild-type mitochondria and was also partially impaired in taz1Δ mitochondria (Figure S2B). The steady-state levels of Oxa1 were also moderately reduced in the mutant mitochondria (Figure 2A). It has been shown that the Oxa1 precursor accumulates as a translocation intermediate at the TOM complex in the absence of a Δψ (the intermediate can be directly visualized by blue native electrophoresis [27Frazier A.E. Chacinska A. Truscott K.N. Guiard B. Pfanner N. Rehling P. Mitochondria use different mechanisms for transport of multispanning membrane proteins through the intermembrane space.Mol. Cell. Biol. 2003; 23: 7818-7828Crossref PubMed Scopus (52) Google Scholar, 28Chacinska A. Lind M. Frazier A.E. Dudek J. Meisinger C. Geissler A. Sickmann A. Meyer H.E. Truscott K.N. Guiard B. et al.Mitochondrial presequence translocase: Switching between TOM tethering and motor recruitment involves Tim21 and Tim17.Cell. 2005; 120: 817-829Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar]), whereas hydrophilic precursor proteins destined for the matrix pass through the TOM complex and do not form stable TOM intermediates on blue native gels. We thus asked whether the alteration of the TOM complex in cardiolipin mutants affected the accumulation of the Oxa1 intermediate. The amount of TOM-Oxa1 intermediate was considerably decreased in crd1Δ mitochondria (and the blue native mobility was altered as expected)" @default.
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• W2074179637 title "Mitochondrial Cardiolipin Involved in Outer-Membrane Protein Biogenesis: Implications for Barth Syndrome" @default.
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