title: Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA.
abstract: Mre11 is a critical participant in upkeep of nuclear DNA, its repair, replication, meiosis, and maintenance of telomeres. The upkeep of mitochondrial DNA (mtDNA) is less well characterized, and whether Mre11 participates has been unknown. We previously found that high NaCl causes some of the Mre11 to leave the nucleus, but we did not then attempt to localize it within the cytoplasm. In the present studies, we find Mre11 in mitochondria isolated from primary renal cells and show that the amount of Mre11 in mitochondria increases with elevation of extracellular NaCl. We confirm the presence of Mre11 in the mitochondria of cells by confocal microscopy and show that some of the Mre11 colocalizes with mtDNA. Furthermore, crosslinking of Mre11 to DNA followed by Mre11 immunoprecipitation directly demonstrates that some Mre11 binds to mtDNA. Abundant Mre11 is also present in tissue sections from normal mouse kidneys, colocalized with mitochondria of proximal tubule and thick ascending limb cells. To explore whether distribution of Mre11 changes with cell differentiation, we used an experimental model of tubule formation by culturing primary kidney cells in Matrigel matrix. In nondifferentiated cells, Mre11 is mostly in the nucleus, but it becomes mostly cytoplasmic upon cell differentiation. We conclude that Mre11 is present in mitochondria where it binds to mtDNA and that the amount in mitochondria varies depending on cellular stress and differentiation. Our results suggest a role for Mre11 in the maintenance of genome integrity in mitochondria in addition to its previously known role in maintenance of nuclear DNA.
authors.affiliation: Laboratory of Kidney and Electrolyte Metabolism,National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. dmitrien@nhlbi.nih.gov
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Dmitrieva
authors.forename: Daniela
authors.initials: D
authors.lastname: Malide
authors.forename: Maurice B
authors.initials: MB
authors.lastname: Burg
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D000076228:MRE11 Homologue Protein; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000201:enzymology*; D009997:Osmotic Pressure; D021381:Protein Transport; D012965:Sodium Chloride / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D012965:Sodium Chloride; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes