Mitochondrial complex I gene variations; as a potential genetic risk factor in pathogenesis of multiple sclerosis

Zonouzi, Ahmad Poursadegh; Ghorbian, Saeid; Abkar, Morteza; Zonouzi, Ali Akbar Poursadegh; Azadi, Ali

doi:10.1016/j.jns.2014.07.051

Cited by 11 publications

(5 citation statements)

References 22 publications

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“…The missense mutations in the ND4 gene observed in Saudi patients with MS in the present study have not been reported in previous studies, at least to the best of our knowledge, and may therefore be considered novel. Since all previous mtDNA studies have revealed a number of variations in MS patients of different populations, such as Caucasians and Filipinos (28,29,48), the identified novel mutations in Saudi patients with MS in the present study could be ethnic-related and may be important to personalized treatment. This study also confirmed the implication of mtDNA mutations in the pathogenicity of MS and the newly identified mutations may serve as a reference for future studies on the mitochondrial genome in MS.…”

Section: Discussionmentioning

confidence: 73%

“…For example, specific variants in the ND2 gene of complex I have been strongly linked to MS in Caucasians (28). Several other variants in different genes of complex I have been shown to be risk factors in the pathogenicity of MS in a Filipino population (29). The study by Yu et al (48) demonstrated an association between the m.13708G>A variant in the ND5 gene and an increased risk of MS in European cohorts.…”

Section: Discussionmentioning

confidence: 99%

“…mtDNA-encoded ND1 , ND2 , ND3 , ND4 , ND4L , ND5 and ND6 genes of complex I were amplified by PCR. The sequences of the primers of the 7 subunits (Table I) were as previously described by Zonouzi et al (29). Each PCR reaction contained 50 ng of DNA, 0.4 µl of each primer, 0.2 µl Super Taq polymerase (Invitrogen; Thermo Fisher Scientific, Inc.), 0.8 µl MgCl 2 , 0.4 µl dNTPs master mix (10 mM of each), and 2.5 µl 10X PCR buffer to a final volume of 25 µl.…”

Section: Methodsmentioning

confidence: 99%

“…Studies on mtDNA in patients with MS from different ethnic backgrounds have identified variations within complex I genes to be associated with the pathogenicity of MS. A specific variant in the ND2 gene of complex I has been reported to play a role in the susceptibility to MS in Caucasians (28). Other variants in different genes of complex I have been shown to be associated with the risk of developing MS in a Filipino population (29). These observations suggest that although the disease etiology is common between populations, genetic variants can be population-specific.…”

Section: Introductionmentioning

confidence: 99%

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Four novel mutations in the mitochondrial ND4 gene of complex�I in patients with multiple sclerosis

et al. 2019

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Multiple sclerosis (MS) is an immune-mediated neurological, inflammatory disease of the central nervous system. Recent studies have suggested that genetic variants in mitochondrial DNA (mtDNA)-encoded complexes of respiratory chain, particularly, complex I (NADH dehydrogenase), contribute to the pathogenicity of MS among different ethnicities, and targeting mitochondrial function may represent a novel approach for MS therapy. In this study, we sequenced ND genes (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6) encoding subunits of complex I in 124 subjects, 60 patients with relapsing-remitting MS and 64 healthy individuals, in order to identify potential novel mutations in these patients. We found several variants in ND genes in both the patients and controls, and specific variants only in patients with MS. While the majority of these variants were synonymous, 4 variants in the ND4 gene were identified as missense mutations in patients with MS. Of these, m.11150G>A was observed in one patient, whereas m.11519A>C, m.11523A>C and m.11527C>T were observed in another patient. Functional analysis predicted the mutations, m.11519A>C, m.11523A>C and m.11150G>A, as deleterious with a direct impact on ND4 protein stability and complex I function, whereas m.11527C>T mutation had no effect on ND4 protein stability. However, the 3 mutations, m.11519A>C, m.11523A>C and m.11527C>T, which were observed in the same patient, were predicted to cause a cumulative destabilizing effect on ND4 protein, and could thus disrupt complex I function. On the whole, this study identified 4 novel mutations in the mtDNA-encoded ND4 gene in patients with MS, which could lead to complex I dysfunction, and further confirmed the implication of mtDNA mutations in the pathogenicity of MS. The identified novel mutations in patients with MS may be ethnic-related and may prove to be significant in personalized treatment.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Four novel mutations in the mitochondrial ND4 gene of complex�I in patients with multiple sclerosis

et al. 2019

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune neuroinflammation triggers mitochondrial oxidation in oligodendrocytes

Steudler

Ecott

Ivan

et al. 2022

Glia

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Oligodendrocytes (ODCs) are myelinating cells of the central nervous system (CNS) supporting neuronal survival. Oxidants and mitochondrial dysfunction have been suggested as the main causes of ODC damage during neuroinflammation as observed in multiple sclerosis (MS). Nonetheless, the dynamics of this process remain unclear, thus hindering the design of neuroprotective therapeutic strategies. To decipher the spatio-temporal pattern of oxidative damage and dysfunction of ODC mitochondria in vivo, we created a novel mouse model in which ODCs selectively express the ratiometric H 2 O 2 biosensor mito-roGFP2-Orp1 allowing for quantification of redox changes in their mitochondria. Using 2-photon imaging of the exposed spinal cord, we observed significant mitochondrial oxidation in ODCs upon induction of the MS model experimental autoimmune encephalomyelitis (EAE). This redox change became already apparent during the preclinical phase of EAE prior to CNS infiltration of inflammatory cells. Upon clinical EAE development, mitochondria oxidation remained detectable and was associated with a significant impairment in organelle density and morphology. These alterations correlated with the proximity of ODCs to inflammatory lesions containing activated microglia/macrophages. During the chronic progression of EAE, ODC mitochondria maintained an altered morphology, but their oxidant levels decreased to levels observed in healthy mice. Taken together, our study implicates oxidative stress in ODC mitochondria as a novel pre-clinical sign of MS-like inflammation and demonstrates that evolving redox and morphological changes in mitochondria accompany ODC dysfunction during neuroinflammation.

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Carbohydrate and lipid metabolism in multiple sclerosis: Clinical implications for etiology, pathogenesis, diagnosis, prognosis, and therapy

Pashaei

Mohammadi

Yarani

et al. 2021

Archives of Biochemistry and Biophysics

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Mitochondrial complex I gene variations; as a potential genetic risk factor in pathogenesis of multiple sclerosis

Cited by 11 publications

References 22 publications

Four novel mutations in the mitochondrial ND4 gene of complex�I in patients with multiple sclerosis

Four novel mutations in the mitochondrial ND4 gene of complex�I in patients with multiple sclerosis

Autoimmune neuroinflammation triggers mitochondrial oxidation in oligodendrocytes

Carbohydrate and lipid metabolism in multiple sclerosis: Clinical implications for etiology, pathogenesis, diagnosis, prognosis, and therapy

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