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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Manninen, Tuula Kislin, Mikhail Hämäläinen, Riikka H. Otonkoski, Timo Suomalainen, Anu Koivumäki, Hanna |
| Description | Author Affiliation: Hämäläinen RH ( Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 38 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA, Mitochondrial Genetics Electron Transport Complex I Metabolism Induced Pluripotent Stem Cells MELAS Syndrome Neurons Blotting, Western Electron Transport Fluorescent Antibody Technique Image Processing, Computer-Assisted Immunohistochemistry Microsatellite Repeats Microscopy, Electron Microscopy, Fluorescence Phagosomes Point Mutation Protein Kinases Statistics, Nonparametric Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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