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PMID: 24003133 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 110 ·No. 38 ·2013-09-17 ·Pages E3622-30

Hämäläinen RH, Manninen T, Koivumäki H, Kislin M, Otonkoski T, Suomalainen A

Abstract

Mitochondrial DNA (mtDNA) mutations manifest with vast clinical heterogeneity. The molecular basis of this variability is mostly unknown because the lack of model systems has hampered mechanistic studies. We generated induced pluripotent stem cells from patients carrying the most common human disease mutation in mtDNA, m.3243A>G, underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. During reprogramming, heteroplasmic mtDNA showed bimodal segregation toward homoplasmy, with concomitant changes in mtDNA organization, mimicking mtDNA bottleneck during epiblast specification. Induced pluripotent stem cell-derived neurons and various tissues derived from teratomas manifested cell-type specific respiratory chain (RC) deficiency patterns. Similar to MELAS patient tissues, complex I defect predominated. Upon neuronal differentiation, complex I specifically was sequestered in perinuclear PTEN-induced putative kinase 1 (PINK1) and Parkin-positive autophagosomes, suggesting active degradation through mitophagy. Other RC enzymes showed normal mitochondrial network distribution. Our data show that cellular context actively modifies RC deficiency manifestation in MELAS and that autophagy is a significant component of neuronal MELAS pathogenesis.

Keywords
disease modeling mitochondria
MeSH Terms
Blotting, Western DNA, Mitochondrial/genetics Electron Transport/genetics Electron Transport Complex I/metabolism Fluorescent Antibody Technique Humans Image Processing, Computer-Assisted Immunohistochemistry Induced Pluripotent Stem Cells/metabolism MELAS Syndrome/genetics,metabolism Microsatellite Repeats/genetics Microscopy, Electron Microscopy, Fluorescence Neurons/metabolism Phagosomes/metabolism Point Mutation/genetics Protein Kinases/metabolism Statistics, Nonparametric
Chemicals
DNA, Mitochondrial Protein Kinases PTEN-induced putative kinase Electron Transport Complex I
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hämäläinen Riikka H
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland.
Manninen Tuula
Koivumäki Hanna
Kislin Mikhail
Otonkoski Timo
Suomalainen Anu
References (56)
56 references, click to expand
  1. Depletion of mitochondrial DNA in leucocytes harbouring the 3243A->G mtDNA mutation.
    J Med Genet. 2007 Jan;44(1):69-74 PMID: 16950816
  2. Mechanisms of mitochondrial diseases.
    Ann Med. 2012 Feb;44(1):41-59 PMID: 21806499
  3. Transmitochondrial mice as models for mitochondrial DNA-based diseases.
    Exp Anim. 2011;60(5):421-31 PMID: 22041279
  4. Abnormalities of the electron transport chain in idiopathic Parkinson's disease.
    Ann Neurol. 1989 Dec;26(6):719-23 PMID: 2557792
  5. Quantification of tRNA3243(Leu) point mutation of mitochondrial DNA in MELAS patients and its effects on mitochondrial transcription.
    Hum Mol Genet. 1993 May;2(5):525-34 PMID: 8518790
  6. Complex I deficiency in Parkinson's disease frontal cortex.
    Brain Res. 2008 Jan 16;1189:215-8 PMID: 18061150
  7. Induced pluripotent stem cells generated from diabetic patients with mitochondrial DNA A3243G mutation.
    Diabetologia. 2012 Jun;55(6):1689-98 PMID: 22396012
  8. Fragmentation and partitioning of the Golgi apparatus during mitosis in HeLa cells.
    EMBO J. 1987 Nov;6(11):3239-46 PMID: 3428259
  9. Mitochondrial rejuvenation after induced pluripotency.
    PLoS One. 2010 Nov 23;5(11):e14095 PMID: 21124794
  10. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.
    Brain. 2007 Nov;130(Pt 11):3032-40 PMID: 17921179
  11. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
    Nature. 1990 Dec 13;348(6302):651-3 PMID: 2102678
  12. Small molecule inhibitors promote efficient generation of induced pluripotent stem cells from human skeletal myoblasts.
    Stem Cells Dev. 2013 Jan 1;22(1):114-23 PMID: 22671711
  13. Alteration in the copy number of mitochondrial DNA in leukocytes of patients with mitochondrial encephalomyopathies.
    Acta Neurol Scand. 2006 May;113(5):334-41 PMID: 16629770
  14. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome.
    Ann Neurol. 1984 Oct;16(4):481-8 PMID: 6093682
  15. MELAS: clinical features, biochemistry, and molecular genetics.
    Ann Neurol. 1992 Apr;31(4):391-8 PMID: 1586140
  16. Bovine complex I is a complex of 45 different subunits.
    J Biol Chem. 2006 Oct 27;281(43):32724-7 PMID: 16950771
  17. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.
    Nat Genet. 1992 Aug;1(5):368-71 PMID: 1284550
  18. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations.
    Science. 2008 Feb 15;319(5865):958-62 PMID: 18276892
  19. Unequal partitioning of bovine mitochondrial genotypes among siblings.
    Proc Natl Acad Sci U S A. 1988 Nov;85(21):8107-10 PMID: 2460862
  20. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes.
    Nat Genet. 2000 Oct;26(2):176-81 PMID: 11017072
  21. Mouse mtDNA mutant model of Leber hereditary optic neuropathy.
    Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):20065-70 PMID: 23129651
  22. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes.
    Nat Genet. 2008 Feb;40(2):249-54 PMID: 18223651
  23. Population prevalence of the MELAS A3243G mutation.
    Mitochondrion. 2007 May;7(3):230-3 PMID: 17300999
  24. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells.
    Nat Genet. 2007 Mar;39(3):386-90 PMID: 17293866
  25. Minimum birth prevalence of mitochondrial respiratory chain disorders in children.
    Brain. 2003 Aug;126(Pt 8):1905-12 PMID: 12805096
  26. Rapid segregation of heteroplasmic bovine mitochondria.
    Nucleic Acids Res. 1989 Sep 25;17(18):7325-31 PMID: 2798094
  27. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
    Nature. 1988 Feb 25;331(6158):717-9 PMID: 2830540
  28. A Balbiani body and the fusome mediate mitochondrial inheritance during Drosophila oogenesis.
    Development. 2003 Apr;130(8):1579-90 PMID: 12620983
  29. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.
    Mol Cell Biol. 1992 Feb;12(2):480-90 PMID: 1732728
  30. The impact of mitochondrial tRNA mutations on the amount of ATP synthase differs in the brain compared to other tissues.
    Biochim Biophys Acta. 2008 May;1782(5):317-25 PMID: 18319067
  31. Clinical features of A3243G mitochondrial tRNA mutation.
    Brain Dev. 2004 Oct;26(7):459-62 PMID: 15351082
  32. The balbiani body: asymmetry in the mammalian oocyte.
    Genesis. 2000 Mar;26(3):208-12 PMID: 10705381
  33. Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck.
    Cell Rep. 2012 May 31;1(5):506-15 PMID: 22701816
  34. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion.
    Hum Mol Genet. 2008 Dec 1;17(23):3822-35 PMID: 18775955
  35. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation.
    Science. 1989 Oct 27;246(4929):500-3 PMID: 2814477
  36. Fatal neonatal lactic acidosis caused by a novel de novo mitochondrial G7453A tRNA-Serine ((UCN)) mutation.
    Pediatr Res. 2012 Jul;72(1):90-4 PMID: 22453297
  37. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes.
    Nat Genet. 2008 Dec;40(12):1484-8 PMID: 19029901
  38. Mouse models of mitochondrial DNA defects and their relevance for human disease.
    EMBO Rep. 2009 Feb;10(2):137-43 PMID: 19148224
  39. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.
    Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17687-92 PMID: 16301523
  40. Pathogenic mitochondrial DNA mutations are common in the general population.
    Am J Hum Genet. 2008 Aug;83(2):254-60 PMID: 18674747
  41. Induced pluripotent stem cells with a mitochondrial DNA deletion.
    Stem Cells. 2013 Jul;31(7):1287-97 PMID: 23400930
  42. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
    Cell. 2007 Nov 30;131(5):861-72 PMID: 18035408
  43. Oculocraniosomatic neuromuscular disease with "ragged-red" fibers.
    Arch Neurol. 1972 Mar;26(3):193-211 PMID: 4400816
  44. Mesencephalic complex I deficiency does not correlate with parkinsonism in mitochondrial DNA maintenance disorders.
    Brain. 2013 Aug;136(Pt 8):2379-92 PMID: 23811324
  45. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.
    Science. 1988 Dec 9;242(4884):1427-30 PMID: 3201231
  46. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts.
    J Child Neurol. 1994 Jan;9(1):4-13 PMID: 8151079
  47. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA.
    Nat Genet. 1996 Oct;14(2):146-51 PMID: 8841183
  48. Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation.
    Neurology. 1997 Jul;49(1):270-3 PMID: 9222207
  49. Human induced pluripotent stem cells harbor homoplasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell-like metabolic reprogramming.
    Stem Cells. 2011 Sep;29(9):1338-48 PMID: 21732474
  50. Premature ageing in mice expressing defective mitochondrial DNA polymerase.
    Nature. 2004 May 27;429(6990):417-23 PMID: 15164064
  51. The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle.
    Am J Hum Genet. 1992 May;50(5):934-49 PMID: 1315123
  52. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation.
    Neurology. 1992 Mar;42(3 Pt 1):545-50 PMID: 1549215
  53. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population.
    Am J Hum Genet. 1998 Aug;63(2):447-54 PMID: 9683591
  54. The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells.
    Stem Cells. 2010 Apr;28(4):721-33 PMID: 20201066
  55. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission.
    Nat Genet. 2012 Nov;44(11):1282-5 PMID: 23042113
  56. Neurogenic neuroepithelial and radial glial cells generated from six human embryonic stem cell lines in serum-free suspension and adherent cultures.
    Glia. 2007 Mar;55(4):385-99 PMID: 17152062
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1311660110
Published
2013-09-17
Epub
2013-00-03
Pages
E3622-30
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3780874
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.1311660110 PMC Full Text View journal details
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