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Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis,

Shihori Kawano1, Chika Saegusa2, Yusuke Masano1

  • 1Department of Molecular Genetics, Kitasato University School of Medicine.

Journal of Visualized Experiments : Jove
|October 27, 2025
PubMed

Insights

Patient-derived brain organoids reveal how mitochondrial disorders like MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) develop. These models aid in understanding disease mechanisms and screening for new drugs.

Area of Science:

  • Neuroscience
  • Genetics
  • Stem Cell Biology

Background:

  • Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a mitochondrial disorder often caused by the m.3243A>G variant.
  • Understanding the pathophysiology of MELAS is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the pathophysiology of MELAS using patient-derived induced pluripotent stem cell (iPSC) brain organoids.
  • To establish a platform for high-throughput drug screening for MELAS.

Main Methods:

  • Generation of iPSC lines from a MELAS patient with the m.3243A>G variant, varying in heteroplasmy levels.
  • Cultivation of brain organoids and subsequent dissociation into 2D neuronal cultures.
  • Evaluation of organoid size, morphology, neural induction efficiency, and neural network formation.

Main Results:

  • Organoid size, morphology, and neural induction efficiency varied significantly with heteroplasmy levels.
  • Neural network formation in 2D cultures also showed heteroplasmy-dependent differences.
  • Patient-derived iPSC brain organoids provide a viable model for MELAS research.

Conclusions:

  • Patient-derived iPSC brain organoids are a valuable tool for studying MELAS mechanisms.
  • This model system facilitates high-throughput drug screening for potential MELAS therapies.

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