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

Mitochondrial disorders (MDs) arise as a result of a respiratory chain dysfunction. While some MDs can affect a single organ, many involve several organs, the brain being the most affected, followed by heart and/or muscle. Many of these diseases are associated with heteroplasmic mutations in the mitochondrial DNA (mtDNA). The proportion of mutated mtDNA must exceed a critical threshold to produce disease. Therefore, understanding how embryonic development determines the heteroplasmy level in each tissue could explain the organ susceptibility and the clinical heterogeneity observed in these patients. In this report, the dynamics of heteroplasmy and the influence in cardiac commitment of the mutational load of the m.13513G>A mutation has been analyzed. This mutation has been reported as a frequent cause of Leigh syndrome (LS) and is commonly associated with cardiac problems. In this report, induced pluripotent stem cell (iPSc) technology has been used to delve into the molecular mechanisms underlying cardiac disease in LS. When mutation m.13513G>A is above a threshold, iPSc‐derived cardiomyocytes (iPSc‐CMs) could not be obtained due to an inefficient epithelial‐mesenchymal transition. Surprisingly, these cells are redirected toward neuroectodermal lineages that would give rise to the brain. However, when mutation is below that threshold, dysfunctional CM are generated in a mutant‐load dependent way. We suggest that distribution of the m.13513G>A mutation during cardiac differentiation is not at random. We propose a possible explanation of why neuropathology is a frequent feature of MD, but cardiac involvement is not always present.The authors are very grateful to Dr. Munell for kindly providing them the patient's fibroblasts. Contract grant sponsor: Instituto de Salud Carlos III (Fondo de Investigación Sanitaria and Regional Development Fund [ERDF/FEDER]); contract grant numbers: PI10/00703, PI13/00556, and PI16/00489 to R. G. and PI15/00484 and PI18/00151 to M. E. G. Contract grant sponsor: Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER); contract grant numbers: (13–717/132.05 and ER16P3AC717 to R. G.). Contract grant sponsor: Miguel Servet Program from ISCIII; contract grant number: CP16/00046 to M. E. G