title: Suppression of mitochondrial DNA instability of autosomal dominant forms of progressive external ophthalmoplegia-associated ANT1 mutations in Podospora anserina.
abstract: Maintenance and expression of mitochondrial DNA (mtDNA) are essential for the cell and the organism. In humans, several mutations in the adenine nucleotide translocase gene ANT1 are associated with multiple mtDNA deletions and autosomal dominant forms of progressive external ophthalmoplegia (adPEO). The mechanisms underlying the mtDNA instability are still obscure. A current hypothesis proposes that these pathogenic mutations primarily uncouple the mitochondrial inner membrane, which secondarily causes mtDNA instability. Here we show that the three adPEO-associated mutations equivalent to A114P, L98P, and V289M introduced into the Podospora anserina ANT1 ortholog dominantly cause severe growth defects, decreased reactive oxygen species production (ROS), decreased mitochondrial inner membrane potential (Deltapsi), and accumulation of large-scale mtDNA deletions leading to premature death. Interestingly, we show that, at least for the adPEO-type M106P and A121P mutant alleles, the associated mtDNA instability cannot be attributed only to a reduced membrane potential or to an increased ROS level since it can be suppressed without restoration of the Deltapsi or modification of the ROS production. Suppression of mtDNA instability due to the M106P and A121P mutations was obtained by an allele of the rmp1 gene involved in nucleo-mitochondrial cross- talk and also by an allele of the AS1 gene encoding a cytosolic ribosomal protein. In contrast, the mtDNA instability caused by the S296M mutation was not suppressed by these alleles.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Génétique Moléculaire, Gif-sur-Yvette F-91198, France.
authors.forename: Riyad
authors.initials: R
authors.lastname: El-Khoury
authors.forename: Annie
authors.initials: A
authors.lastname: Sainsard-Chanet
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D005804:Genes, Lethal / Q000235:genetics; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics; D048468:Podospora / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D033741:Adenine Nucleotide Translocator 1; D004272:DNA, Mitochondrial; D005656:Fungal Proteins; D017382:Reactive Oxygen Species; D000226:Mitochondrial ADP, ATP Translocases
references.citation: Curr Genet. 1998 Oct;34(4):326-35
references.pmid: 9799367
references.citation: J Biol Chem. 1992 Jul 25;267(21):14592-7
references.pmid: 1378836
references.citation: J Biol Chem. 1994 May 27;269(21):14951-6
references.pmid: 8195128
references.citation: Mol Cell Biol. 1999 Jun;19(6):4093-100
references.pmid: 10330149
references.citation: J Mol Biol. 2007 Aug 10;371(2):388-95
references.pmid: 17572439
references.citation: Nat Genet. 1997 Jul;16(3):226-34
references.pmid: 9207786
references.citation: Biogerontology. 2001;2(1):1-17
references.pmid: 11708613
references.citation: Genetics. 1996 Oct;144(2):541-55
references.pmid: 8889519
references.citation: Hum Mol Genet. 2002 Aug 1;11(16):1835-43
references.pmid: 12140186
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4138-43
references.pmid: 10759557
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4820-5
references.pmid: 10220377
references.citation: Genome Biol. 2008;9(5):R77
references.pmid: 18460219
references.citation: FEBS Lett. 1975 Aug 1;56(1):192-32
references.pmid: 1157932
references.citation: Genetics. 2004 Jun;167(2):607-17
references.pmid: 15238515
references.citation: Proc Natl Acad Sci U S A. 1991 May 1;88(9):3579-83
references.pmid: 2023905
references.citation: Neuromuscul Disord. 2003 Feb;13(2):162-5
references.pmid: 12565915
references.citation: Mol Microbiol. 2001 Dec;42(5):1259-67
references.pmid: 11886557
references.citation: Genetics. 2004 Jan;166(1):135-50
references.pmid: 15020413
references.citation: Eukaryot Cell. 2004 Feb;3(1):200-11
references.pmid: 14871950
references.citation: Fungal Genet Biol. 2007 Jul;44(7):648-58
references.pmid: 17081785
references.citation: Am J Hum Genet. 1999 Jul;65(1):256-61
references.pmid: 10364542
references.citation: Biogerontology. 2002;3(3):143-53
references.pmid: 12075133
references.citation: FEBS Lett. 2005 Jan 31;579(3):633-7
references.pmid: 15670820
references.citation: Hum Mol Genet. 2004 May 1;13(9):923-34
references.pmid: 15016764
references.citation: Genetics. 2000 Jun;155(2):657-69
references.pmid: 10835389
references.citation: Biochim Biophys Acta. 2008 Oct;1778(10):1978-2021
references.pmid: 18510943
references.citation: Annu Rev Med. 2008;59:131-46
references.pmid: 17892433
references.citation: Curr Genet. 1994 Feb;25(2):122-3
references.pmid: 8087879
references.citation: Biochemistry. 2002 Dec 3;41(48):14412-20
references.pmid: 12450408
references.citation: Ann Neurol. 2002 May;51(5):645-8
references.pmid: 12112115
references.citation: Science. 2000 Aug 4;289(5480):782-5
references.pmid: 10926541
references.citation: Neurology. 2001 Dec 26;57(12):2295-8
references.pmid: 11756613
references.citation: Curr Genet. 2008 Apr;53(4):249-58
references.pmid: 18265986
references.citation: Nat Cell Biol. 2008 Sep;10(9):1090-7
references.pmid: 19160490
references.citation: Mol Biol Cell. 2008 Sep;19(9):3934-43
references.pmid: 18614795
references.citation: Curr Genet. 1990 May;17(5):375-402
references.pmid: 2357736
references.citation: Trends Genet. 2003 Feb;19(2):60-2
references.pmid: 12547509
references.citation: Hum Mol Genet. 2005 Oct 15;14(20):3079-88
references.pmid: 16155110
references.citation: Biochem Genet. 1981 Aug;19(7-8):729-40
references.pmid: 7295296
references.citation: Annu Rev Biochem. 2006;75:713-41
references.pmid: 16451122
references.citation: Biochimie. 1998 Feb;80(2):137-50
references.pmid: 9587671
references.citation: Hum Mol Genet. 2008 Dec 15;17(24):4036-44
references.pmid: 18809618
references.citation: Pflugers Arch. 2004 Feb;447(5):689-709
references.pmid: 14598172
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8271-6
references.pmid: 10393984
references.citation: EMBO J. 1984 Feb;3(2):377-82
references.pmid: 6325169
references.citation: J Gen Microbiol. 1989 Mar;135(3):601-4
references.pmid: 2621442