Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane

Defined mutations in the mitochondrial ADP/ATP carrier (AAC) are associated with certain types of progressive external ophthalmoplegia. AAC is required for oxidative phosphorylation (OXPHOS), and dysregulation of AAC has been implicated in apoptosis. Little is known about the AAC interactome, aside from a known requirement for the phospholipid cardiolipin (CL) and that it is thought to function as a homodimer. Using a newly developed dual affinity tag, we demonstrate that yeast AAC2 physically participates in several protein complexes of distinct size and composition. The respiratory supercomplex and several smaller AAC2-containing complexes, including other members of the mitochondrial carrier family, are identified here. In the absence of CL, most of the defined interactions are destabilized or undetectable. The absence of CL and/or AAC2 results in distinct yet additive alterations in respiratory supercomplex structure and respiratory function. Thus, a single lipid can significantly alter the functional interactome of an individual protein.

[1]  E. Boekema,et al.  A Structural Model of the Cytochrome c Reductase/Oxidase Supercomplex from Yeast Mitochondria* , 2007, Journal of Biological Chemistry.

[2]  B. Zhivotovsky,et al.  Role of cardiolipin in cytochrome c release from mitochondria , 2007, Cell Death and Differentiation.

[3]  M. Schlame,et al.  The Enzymatic Function of Tafazzin* , 2006, Journal of Biological Chemistry.

[4]  S. Claypool,et al.  Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins , 2006, The Journal of cell biology.

[5]  Xianlin Han,et al.  Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction. , 2005, Biochemistry.

[6]  M. Zeviani,et al.  Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy. , 2005, Human molecular genetics.

[7]  J. D. Sharer.  The adenine nucleotide translocase type 1 (ANT1): A new factor in mitochondrial disease , 2005, IUBMB life.

[8]  P. Rehling,et al.  Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth Syndrome. , 2005, Molecular biology of the cell.

[9]  William Dowhan,et al.  Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria* , 2005, Journal of Biological Chemistry.

[10]  R. Wanders,et al.  The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome. , 2004, The Journal of biological chemistry.

[11]  V. Tiranti,et al.  Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability. , 2004, Human molecular genetics.

[12]  Kathy Pfeiffer,et al.  Cardiolipin Stabilizes Respiratory Chain Supercomplexes* , 2003, Journal of Biological Chemistry.

[13]  W. Dowhan,et al.  Cardiolipin Is Not Required to Maintain Mitochondrial DNA Stability or Cell Viability for Saccharomyces cerevisiae Grown at Elevated Temperatures* , 2003, Journal of Biological Chemistry.

[14]  I. Sinning,et al.  Choline head groups stabilize the matrix loop regions of the ATP/ADP carrier ScAAC2. , 2003, Biochemical and biophysical research communications.

[15]  M. L. Greenberg,et al.  Absence of Cardiolipin in the crd1 Null Mutant Results in Decreased Mitochondrial Membrane Potential and Reduced Mitochondrial Function* , 2000, The Journal of Biological Chemistry.

[16]  R A Stuart,et al.  The Cytochrome bc 1 and Cytochromec Oxidase Complexes Associate to Form a Single Supracomplex in Yeast Mitochondria* , 2000, The Journal of Biological Chemistry.

[17]  V. Koshkin,et al.  Oxidative phosphorylation in cardiolipin-lacking yeast mitochondria. , 2000, The Biochemical journal.

[18]  M. L. Greenberg,et al.  The biosynthesis and functional role of cardiolipin. , 2000, Progress in lipid research.

[19]  K. Pfeiffer,et al.  Supercomplexes in the respiratory chains of yeast and mammalian mitochondria , 2000, The EMBO journal.

[20]  W. Oppliger,et al.  Tim18p, a New Subunit of the TIM22 Complex That Mediates Insertion of Imported Proteins into the Yeast Mitochondrial Inner Membrane , 2000, Molecular and Cellular Biology.

[21]  N. C. Robinson,et al.  Phospholipase A(2) digestion of cardiolipin bound to bovine cytochrome c oxidase alters both activity and quaternary structure. , 1999, Biochemistry.

[22]  L. Grivell,et al.  The Respiratory Chain in Yeast Behaves as a Single Functional Unit* , 1998, The Journal of Biological Chemistry.

[23]  D. Nelson,et al.  Probing the role of positive residues in the ADP/ATP carrier from yeast. The effect of six arginine mutations on transport and the four ATP versus ADP exchange modes. , 1996, Biochemistry.

[24]  D. Nelson,et al.  Probing the role of positive residues in the ADP/ATP carrier from yeast. The effect of six arginine mutations of oxidative phosphorylation and AAC expression. , 1996, Biochemistry.

[25]  K. Beyer,et al.  Specific cardiolipin binding interferes with labeling of sulfhydryl residues in the adenosine diphosphate/adenosine triphosphate carrier protein from beef heart mitochondria. , 1996, Biochemistry.

[26]  A. Shevchenko,et al.  Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. , 1996, Analytical chemistry.

[27]  P. Philippsen,et al.  New heterologous modules for classical or PCR‐based gene disruptions in Saccharomyces cerevisiae , 1994, Yeast.

[28]  B. Hoffmann,et al.  The reconstituted ADP/ATP carrier activity has an absolute requirement for cardiolipin as shown in cysteine mutants. , 1994, The Journal of biological chemistry.

[29]  J. E. Lawson,et al.  Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential. , 1993, Journal of molecular biology.

[30]  M. Schlame,et al.  Cardiolipin is synthesized on the matrix side of the inner membrane in rat liver mitochondria. , 1993, The Journal of biological chemistry.

[31]  S. Ho,et al.  Site-directed mutagenesis by overlap extension using the polymerase chain reaction. , 1989, Gene.

[32]  M. Klingenberg,et al.  Molecular weight and hydrodynamic parameters of the adenosine 5'-diphosphate--adenosine 5'-triphosphate carrier in Triton X-100. , 1980, Biochemistry.

[33]  M. Klingenberg,et al.  Modulation of the reconstituted adenine nucleotide exchange by membrane potential. , 1980, Biochemistry.

[34]  G. Sparagna,et al.  Role of cardiolipin alterations in mitochondrial dysfunction and disease. , 2007, American journal of physiology. Cell physiology.

[35]  D. Brdiczka,et al.  The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis. , 2003, Acta biochimica Polonica.

[36]  W. Oppliger,et al.  Tim 18 p , a New Subunit of the TIM 22 Complex That Mediates Insertion of Imported Proteins into the Yeast Mitochondrial Inner Membrane , 2000 .

[37]  thematic review Thematic Review Series: Glycerolipids , 2022 .