title: Folate deficiency increases mtDNA and D-1 mtDNA deletion in aged brain of mice lacking uracil-DNA glycosylase.
abstract: Strong epidemiological and experimental evidence links folate deficiency and resultant hyperhomocysteinemia with cognitive decline and neurodegeneration. Here, we tested the hypothesis that uracil misincorporation contributes to mitochondrial pathology in aged brain following folate deprivation. In a 2 × 2 design, 14-month-old mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls were subjected to a folate-deficient versus a regular diet for six weeks. Folate-deficient feeding significantly enhanced mtDNA content and overall abundance of the D-1 mtDNA deletion in brain of Ung-/-, but not of wild-type mice. Independent of folate status, the frequency of the D-1 mtDNA deletion in mtDNA was significantly increased in Ung-/- mice. The rate of mitochondrial biogenesis as assessed at six weeks of the experimental diet by mRNA expression levels of transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and of mitochondrial transcription factor A (Tfam) was not affected by either Ung-/- genotype or short-term folate deficiency. Similarly, citrate synthase (CS) activity in the brain did not differ across experimental groups. By contrast, independent of genotype, lactate dehydrogenase (LDH) activity was significantly reduced in folate-deficient animals. Our results suggest that impaired uracil excision repair causes an increase in mitochondrial mutagenesis in aged brain along with a compensatory increase in mtDNA content in response to low folate status. Folate deficiency may contribute to neurodegeneration via mtDNA damage.
authors.affiliation: Klinik und Hochschulambulanz für Psychiatrie und Psychotherapie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany.
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Rupert W
authors.initials: RW
authors.lastname: Overall
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.forename: Jeanette
authors.initials: J
authors.lastname: Klein
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Page
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Stuart
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001927:Brain Diseases / Q000150:complications / Q000201:enzymology / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005494:Folic Acid Deficiency / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D051981:Uracil-DNA Glycosidase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D051981:Uracil-DNA Glycosidase