Implications of mitochondrial DNA alterations in brain disorders

Identifier:  TDX:4387

Handle: https://hdl.handle.net/20.500.11797/TDX4387

Authors:  Bulduk, Bengisu Kevser

Abstract:
There is increasing evidence that mitochondrial dysfunction may be involved in brain disorders and that changes in mitochondrial DNA may play a role. The aim of this thesis was to identify mtDNA alterations in brain disorders and investigate the differences in the occurrence of these alterations between disease and control populations. Firstly, a systematic review of reported mtDNA alterations in the post-mortem human brain was presented. We then investigated, mtDNA changes in blood samples from patients with intellectual disability (ID) and ID with comorbid autism spectrum disorders (ID-ASD) and healthy controls (HC), and in post-mortem brain tissue from patients with schizophrenia (SZ) and HC. MtDNA alterations have been mainly studied in individuals with mitochondrial disorders (MitD), neurological disorders (NeuD), psychiatric disorders (PsyD), and ageing. We reported that pathogenic single nucleotide variants (pSNVs) present in MitD show different levels of heteroplasmy between brain regions, while being less common in NeuD, PsyD, and ageing. Lower mtDNA copy number (mtDNA-CN) was mainly associated with NeuD, with some exceptions. In addition, mtDNA deletions were found in all disease groups and in ageing, with higher percentages of heteroplasmy in brain than blood samples. In blood samples, patients with ID had more mtDNA rearrangements with low levels of heteroplasmy (1.1-6.7%) compared to HC, suggesting that these alterations may be present with higher levels of heteroplasmy in the brain. In postmortem tissue from SZ patients and HC, we reported a significantly higher number of deletions and likely pathogenic SNV in SZ compared to HC. In addition, a SZ patients had the MitD-associated variant, m.3243 A>G, with a high heteroplasmy level of 32.2%. Taking together, these findings provide additional evidence for the potential involvement of mtDNA alterations in the pathophysiology of brain disorders.