title: The mitochondrial fatty acid synthesis (mtFASII) pathway is capable of mediating nuclear-mitochondrial cross talk through the PPAR system of transcriptional activation.
abstract: Mammalian cells contain two fatty acid synthesis pathways, the cytosolic FASI pathway, and the mitochondrial FASII pathway. The selection behind the conservation of the mitochondrial pathway is not completely understood, given the presence of the cytosolic FAS pathway. In this study, we show through heterologous gene reporter systems and PCR-based arrays that overexpression of MECR, the last step in the mtFASII pathway, causes modulation of gene expression through the PPAR pathway. Electromobility shift assays (EMSAs) demonstrate that overexpression of MECR causes increased binding of PPARs to DNA, while cell fractionation and imaging studies show that MECR remains localized to the mitochondria. Interestingly, knock down of the mtFASII pathway lessens the effect of MECR on this transcriptional modulation. Our data are most consistent with MECR-mediated transcriptional activation through products of the mtFASII pathway, although we cannot rule out MECR acting as a coactivator. Further investigation into the physiological relevance of this communication will be necessary to better understand some of the phenotypic consequences of deficits in this pathway observed in animal models and human disease.
authors.affiliation: Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Parl
authors.forename: Sabrina L
authors.initials: SL
authors.lastname: Mitchell
authors.forename: Hayley B
authors.initials: HB
authors.lastname: Clay
authors.forename: Sara
authors.initials: S
authors.lastname: Reiss
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Murdock
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D005227:Fatty Acids; D047492:Peroxisome Proliferator-Activated Receptors; D044925:Oxidoreductases Acting on CH-CH Group Donors; C434934:trans-2-enoyl-CoA reductase (NADPH)
keywords: ACP; Fatty acid synthesis; MECR; Mitochondria; PPAR; Transcription