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Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels

Masaki Kodaira1, Hideyuki Hatakeyama2, Shinsuke Yuasa1

  • 1Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

FEBS Open Bio
|April 9, 2015
PubMed

Insights

Researchers generated induced pluripotent stem cells (iPSCs) from patients with mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). These MELAS-iPSCs serve as valuable models for studying mitochondrial diseases.

Area of Science:

  • Genetics and Genomics
  • Cell Biology
  • Biomedical Research

Background:

  • Mitochondrial diseases stem from mitochondrial dysfunction, impacting cellular energy production.
  • These disorders arise from mutations in both nuclear and mitochondrial DNA, complicating therapeutic development.
  • Effective disease models are crucial for understanding and treating mitochondrial disorders.

Purpose of the Study:

  • To generate induced pluripotent stem cells (iPSCs) specific to Mitochondrial Myopathy, Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS).
  • To validate the utility of these MELAS-iPSCs as disease models for mitochondrial dysfunction.
  • To investigate the correlation between heteroplasmy levels and cellular function in MELAS-iPSC derivatives.

Main Methods:

  • Established induced pluripotent stem cells (iPSCs) from MELAS patient-derived fibroblasts.
  • Quantified the m.3243A>G heteroplasmy levels across established MELAS-iPSC lines.
  • Assessed the enzymatic activity of mitochondrial respiratory chain complexes in differentiated MELAS-iPSC-derived fibroblasts.

Main Results:

  • Successfully generated MELAS-iPSC lines with a wide range of m.3243A>G heteroplasmy (3.6% to 99.4%).
  • MELAS-iPSC-derived fibroblasts with high heteroplasmy exhibited significant Complex I deficiency.
  • MELAS-iPSC-derived fibroblasts with low heteroplasmy maintained normal Complex I activity.

Conclusions:

  • MELAS-specific iPSCs are viable models for studying MELAS and other mitochondrial diseases.
  • Careful selection of MELAS-iPSCs based on heteroplasmy levels and respiratory function is essential for accurate disease modeling.
  • This study provides a foundation for developing targeted therapies for mitochondrial disorders using patient-specific iPSC models.
Keywords:
Disease modelingEB, embryoid bodyES, embryonic stemKSR, Knock-out Serum ReplacementMEF, mouse embryonic fibroblastMELASMELAS, mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodesMitochondrial diseaseOXPHOS, oxidative phosphorylation systembFGF, basic fibroblast growth factoriPS celliPSCs, induced pluripotent stem cellsmtDNA, mitochondrial DNA

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