Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system with genetics and environmental determinants. Studies focused on the neurogenetics of MS showed that mitochondrial DNA (mtDNA) mutations that can ultimately lead to mitochondrial dysfunction, alter brain energy metabolism and cause neurodegeneration. We analyzed the whole mitochondrial genome using next-generation sequencing (NGS) from 47 Saudi individuals, 23 patients with relapsing-remitting MS and 24 healthy controls to identify mtDNA disease-related mutations/variants. A large number of variants were detected in the D-loop and coding genes of mtDNA. While distinct unique variants were only present in patients or only occur in controls, a number of common variants were shared among the two groups. The prevalence of some common variants differed significantly between patients and controls, thus could be implicated in susceptibility to MS. Of the unique variants only present in the patients, 34 were missense mutations, located in different mtDNA-encoded genes. Seven of these mutations were not previously reported in MS, and predicted to be deleterious with considerable impacts on the functions and structures of encoded-proteins and may play a role in the pathogenesis of MS. These include two heteroplasmic mutations namely 10237T>C in MT-ND3 gene and 15884G>C in MT-CYB gene; and three homoplasmic mutations namely 9288A>G in MT-CO3 gene, 14484T>C in MT-ND6 gene, 15431G>A in MT-CYB gene, 8490T>C in MT-ATP8 gene and 5437C>T in MT-ND2 gene. Notably some patients harboured multiple mutations while other patients carried the same mutations. This study is the first to sequence the entire mitochondrial genome in MS patients in an Arab population. Our results expanded the mutational spectrum of mtDNA variants in MS and highlighted the efficiency of NGS in population-specific mtDNA variant discovery. Further investigations in a larger cohort are warranted to confirm the role of mtDNA MS.

Autoimmune neuroinflammation triggers mitochondrial oxidation in oligodendrocytes

“…In certain MS lesions, ODCs were found to lack the COX‐I and COX‐IV mitochondrial subunit, an alteration potentially caused by NO and indicative of impaired oxidative phosphorylation (Mahad et al, 2008). Analysis of mitochondrial DNA also showed the presence of mutations specific to MS patients in genes encoding for functional proteins including COX‐I (Al‐Kafaji et al, 2022; Poursadegh Zonouzi et al, 2014).…”

Neurodegeneration in Multiple Sclerosis: The Role of Nrf2-Dependent Pathways

“…As mentioned, MS is an etiologically unknown disease leading to neurological disabilities by demyelination in central white matter observed in young adults between the age of 20–40 [ 48 ]. Although studies continue to elucidate the causes, symptoms, and characteristics of MS, recent findings have shown that mitochondrial dysfunction plays a pivotal role in the onset and progression of MS and their related pre-clinical animal models ( Figure 1 ) [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]; for revision see [ 55 ].…”

“…Mitochondrial impairment has been associated with axonal degeneration followed by demyelination in MS [ 50 , 52 ]. An observation of post mortem MS brain tissues showed an impaired axoplasm, reduced organelle content, and fragmented neurofilaments compared with age-match healthy brain samples [ 56 ].…”

“…Oxidative stress induces abundant mitochondrial protein nitration associated with mitochondrial bioenergetics failure and mitochondrial DNA (mitoDNA) mutations, and triggering apoptosis in MS brains [ 50 , 64 , 65 ]. Furthermore, an analysis of cortical slices of MS brain showed a significant presence of oxidative damage, which contributed to axonal demyelination in neurons and oligodendrocytes being more sensitive than astrocytes and microglia [ 66 ].…”

Mitochondrial DNA haplogroup analysis in Saudi Arab patients with multiple sclerosis

“…We recently sequenced the entire mitochondrial genome from unrelated native Saudi Arab individuals including patients with RRMS and healthy controls using next-generation sequencing (NGS), and identified unique and common mtDNA mutations/variants [ 32 ]. In this study, we assessed the hypothesis that mtDNA haplogroup and polymorphisms maybe an important factor in the susceptibility of MS.…”