Mitochondrial DNA deletions are frequent in leukocytes of subjects with intellectual disability

Identifier:  TFG:3042

Handle: https://hdl.handle.net/20.500.11797/TFG3042

Authors:  Torres Egurrola, Leire

Abstract:
Mitochondria are cellular organelles which the main function is the production of energy in ATP form. Mitochondrial dysfunction has been reported in many neurodevelopmental disorders, including autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia (SCZ). Mitochondrial DNA (mtDNA) rearrangements, like deletions, may have a great impact in the mitochondrial correct function leading to oxidative phosphorylation system (OXPHOS) deficiency and, finally, driving to mitochondrial dysfunction. Methods: MtDNA of leukocytes from 85 individuals with ID, 97 patients with ID and ASD (ID-ASD), 56 individuals with SCZ and 39 healthy controls (HC) was analyzed by next-generation sequencing in combination with the eKLIPse bioinformatic tool to detect and quantify mtDNA rearrangements. Results: Results showed that mtDNA deletions in blood were frequent in individuals with ID and ID-ASD (17.7% and 9.3%, respectively), whereas such deletions were not common in both SCZ (1.8%), and HC (2.6%). Also, the removal of the origin of replication of the heavy strand (OH) was more detrimental than the deletion of the origin of replication of the light strand (OL), which was strongly correlated with ID severity and higher CARS scores in ID and ID-ASD patients. Nevertheless, heteroplasmy levels in leukocytes were low, not higher than 5% across all samples. Conclusions: ID severity and CARS score were associated with the presence of large mtDNA deletions in blood and positively correlated with the lack of the OH. Further studies evaluating the involvement of mitochondrial rearrangements in post-mitotic tissues in neurodevelopmental disorders, especially ID, will help to clarify whether these mtDNA deletions detected in blood are present in higher heteroplasmy levels in these tissues.