The mutation m.13513G>A impairs cardiac function, favoring a neuroectoderm commitment, in a mutant-load dependent way

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Cardiology

Background:

• Mitochondrial disorders (MDs) stem from respiratory chain dysfunction, often involving multiple organs like the brain, heart, and muscle.
• Heteroplasmic mutations in mitochondrial DNA (mtDNA) cause MDs, with disease manifestation dependent on exceeding a critical mutation threshold.
• Understanding heteroplasmy dynamics during embryonic development is key to explaining organ susceptibility and clinical heterogeneity in MDs.

Purpose of the Study:

• To analyze heteroplasmy dynamics and the impact of the m.13513G>A mutation load on cardiac commitment.
• To investigate the molecular mechanisms of cardiac disease in Leigh syndrome (LS) using induced pluripotent stem cells (iPSCs).

Main Methods:

• Utilized induced pluripotent stem cell (iPSC) technology to model LS.
• Analyzed the m.13513G>A mutation's effect on cardiomyocyte differentiation and lineage commitment.
• Assessed heteroplasmy levels and their influence on epithelial-mesenchymal transition and cell fate.

Main Results:

• High m.13513G>A mutation loads (above threshold) prevented iPSC-derived cardiomyocyte (iPSC-CM) generation due to impaired epithelial-mesenchymal transition.
• Cells with high mutation loads were unexpectedly redirected towards neuroectodermal lineages, favoring brain development.
• Lower mutation loads resulted in the generation of dysfunctional iPSC-CMs in a mutant-load-dependent manner.
• The distribution of the m.13513G>A mutation during cardiac differentiation was non-random.

Conclusions:

• The study proposes a mechanism explaining the frequent neuropathology in MDs while cardiac involvement is variable.
• Non-random mutation distribution during cardiac differentiation influences cell fate and disease presentation.
• iPSC technology provides insights into the complex interplay between mtDNA mutation load, cell differentiation, and organ-specific pathology in MDs.