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

Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):E3622-30. doi: 10.1073/pnas.1311660110. Epub 2013 Sep 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

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*
  • MELAS Syndrome / metabolism
  • Microsatellite Repeats / genetics
  • Microscopy, Electron
  • Microscopy, Fluorescence
  • Neurons / metabolism*
  • Phagosomes / metabolism
  • Point Mutation / genetics
  • Protein Kinases / metabolism
  • Statistics, Nonparametric


  • DNA, Mitochondrial
  • Protein Kinases
  • PTEN-induced putative kinase
  • Electron Transport Complex I