The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis

Mitochondrial fatty acid synthesis (FASII) and iron sulfur cluster (FeS) biogenesis are both vital biosynthetic processes within mitochondria. In this study, we demonstrate that the mitochondrial acyl carrier protein (ACP), which has a well-known role in FASII, plays an unexpected and evolutionarily conserved role in FeS biogenesis. ACP is a stable and essential subunit of the eukaryotic FeS biogenesis complex. In the absence of ACP, the complex is destabilized resulting in a profound depletion of FeS throughout the cell. This role of ACP depends upon its covalently bound 4’-phosphopantetheine (4-PP)-conjugated acyl chain to support maximal cysteine desulfurase activity. Thus, it is likely that ACP is not simply an obligate subunit but also exploits the 4-PP-conjugated acyl chain to coordinate mitochondrial fatty acid and FeS biogenesis. DOI: http://dx.doi.org/10.7554/eLife.17828.001

[1]  Edward L. Huttlin,et al.  The BioPlex Network: A Systematic Exploration of the Human Interactome , 2015, Cell.

[2]  M. Radermacher,et al.  The LYR protein subunit NB4M/NDUFA6 of mitochondrial complex I anchors an acyl carrier protein and is essential for catalytic activity , 2014, Proceedings of the National Academy of Sciences.

[3]  D. Winge,et al.  Late-Stage Maturation of the Rieske Fe/S Protein: Mzm1 Stabilizes Rip1 but Does Not Facilitate Its Translocation by the AAA ATPase Bcs1 , 2012, Molecular and Cellular Biology.

[4]  D. Winge,et al.  The LYR Protein Mzm1 Functions in the Insertion of the Rieske Fe/S Protein in Yeast Mitochondria , 2011, Molecular and Cellular Biology.

[5]  K. Autio,et al.  Mitochondrial fatty acid synthesis and respiration. , 2010, Biochimica et biophysica acta.

[6]  C. Hunte,et al.  Characterization of two different acyl carrier proteins in complex I from Yarrowia lipolytica. , 2010, Biochimica et biophysica acta.

[7]  A. Witkowski,et al.  Down-regulation of Mitochondrial Acyl Carrier Protein in Mammalian Cells Compromises Protein Lipoylation and Respiratory Complex I and Results in Cell Death* , 2009, Journal of Biological Chemistry.

[8]  A. Kastaniotis,et al.  Intersection of RNA Processing and the Type II Fatty Acid Synthesis Pathway in Yeast Mitochondria , 2008, Molecular and Cellular Biology.

[9]  H. Prokisch,et al.  The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria , 2006, The EMBO journal.

[10]  N. Pfanner,et al.  Essential role of Isd11 in mitochondrial iron–sulfur cluster synthesis on Isu scaffold proteins , 2006, The EMBO journal.

[11]  H. Schägger,et al.  Blue native PAGE , 2006, Nature Protocols.

[12]  N. Maeda,et al.  Endogenous Production of Lipoic Acid Is Essential for Mouse Development , 2005, Molecular and Cellular Biology.

[13]  A. Joshi,et al.  Cloning, expression, and characterization of the human mitochondrial beta-ketoacyl synthase. Complementation of the yeast CEM1 knock-out strain. , 2005, The Journal of biological chemistry.

[14]  D. Winge,et al.  Activation of the Iron Regulon by the Yeast Aft1/Aft2 Transcription Factors Depends on Mitochondrial but Not Cytosolic Iron-Sulfur Protein Biogenesis* , 2005, Journal of Biological Chemistry.

[15]  K. Sipos,et al.  Biogenesis of cytosolic ribosomes requires the essential iron–sulphur protein Rli1p and mitochondria , 2005, The EMBO journal.

[16]  K. Sipos,et al.  Functional Characterization of the Eukaryotic Cysteine Desulfurase Nfs1p from Saccharomyces cerevisiae* , 2004, Journal of Biological Chemistry.

[17]  M. Bard,et al.  Transcription of the Yeast Iron Regulon Does Not Respond Directly to Iron but Rather to Iron-Sulfur Cluster Biosynthesis* , 2004, Journal of Biological Chemistry.

[18]  J. Hirst,et al.  Analysis of the Subunit Composition of Complex I from Bovine Heart Mitochondria*S , 2003, Molecular & Cellular Proteomics.

[19]  S. Garland,et al.  Saccharomyces cerevisiae ISU1 and ISU2: members of a well-conserved gene family for iron-sulfur cluster assembly. , 1999, Journal of molecular biology.

[20]  R. Lill,et al.  The Essential Role of Mitochondria in the Biogenesis of Cellular Iron-Sulfur Proteins , 1999, Biological chemistry.

[21]  E. Schweizer,et al.  A Novel Phosphopantetheine:Protein Transferase Activating Yeast Mitochondrial Acyl Carrier Protein* , 1998, The Journal of Biological Chemistry.

[22]  S. Brody,et al.  Mitochondrial acyl carrier protein is involved in lipoic acid synthesis in Saccharomyces cerevisiae , 1997, FEBS letters.

[23]  H. Weiss,et al.  The acyl-carrier protein in Neurospora crassa mitochondria is a subunit of NADH:ubiquinone reductase (complex I). , 1991, European journal of biochemistry.

[24]  P. Majerus,et al.  ACYL CARRIER PROTEIN. IV. THE IDENTIFICATION OF 4'-PHOSPHOPANTETHEINE AS THE PROSTHETIC GROUP OF THE ACYL CARRIER PROTEIN. , 1965, Proceedings of the National Academy of Sciences of the United States of America.