A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging

Schauer, Marianne; Kottek, Tina; Schönherr, Madeleine; Bhattacharya, Animesh; Ibrahim, Saleh M.; Hirose, Misa; Köhling, Rüdiger; Fuellen, Georg; Schmitz, Ulf; Kunz, Manfred

doi:10.18632/oncotarget.3298

Cited by 13 publications

(11 citation statements)

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“…The mtALR strain harbors a SNP at position nt4738 (4738C>A) in gene MT-ND2 , causing an Leu-Met amino acid exchange in NADH coenzyme Q oxidoreductase chain 2. This mutation leads to a more than twofold up-regulation of enzyme activity and increased ATP production, at least in fibroblasts, and, further, to accelerated ageing in these fibroblasts [ 30 ]. Complex III is represented by C57BL/6J-mt 129S1/SvlmJ (mt129S1) carrying a SNP at nt15124 (15124A>G) affecting MT-CYTB which leads to an alteration of cytochrome bc1 complex III (Ile-Val exchange).…”

Section: Methodsmentioning

confidence: 99%

Reduced Adolescent-Age Spatial Learning Ability Associated with Elevated Juvenile-Age Superoxide Levels in Complex I Mouse Mutants

et al. 2015

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Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities. The functional impact of homoplasmic specific mtDNA point mutations, e.g., in genes coding for the electron transport chain, however, remains a matter of debate. The present study contributes to this discussion and provides evidence that a single point mutation in complex I of the respiratory chain is associated with impairment of spatial navigation in adolescent (6-month-old) mice, i.e., reduced performance in the Morris Water Maze, which goes along with increased production of reactive oxygen species (ROS) in juvenile mice (3 months) but not at the age of phenotype expression. A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production. These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.

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Section: Methodsmentioning

confidence: 99%

Reduced Adolescent-Age Spatial Learning Ability Associated with Elevated Juvenile-Age Superoxide Levels in Complex I Mouse Mutants

et al. 2015

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“…For example, conplastic rats where shown to have impaired glucose tolerance, while mice were more resistant to experimental autoimmune encephalomyelitis [51], had disrupted activity of the components of TCA cycle [52] or altered mitochondrial and cellular adaptation during aging [53]. Moreover, the mutation in MT-ND2 gene (C4738A) in mouse fibroblasts led to significantly higher mitochondrial complex I activity, enhanced ATP production, reduced ROS production with similar MT-ND2 protein expression levels [54]. A lot of studies have shown that even a point mutation in mitochondrial genome which was introduced onto another nuclear background led to severe mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial GWAS and association of nuclear – mitochondrial epistasis with BMI in T1DM patients

et al. 2020

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Background: BMI is a strong indicator of complications from type I diabetes, especially under intensive treatment. Methods: We have genotyped 435 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We identified additive interactions between mitochondrial and nuclear variants in genes associated with mitochondrial functioning MitoCarta2.0 and confirmed and refined the results on external cohorts: the Framingham Heart Study (FHS) and GTEx data. Linear mixed model analysis was performed using the GENESIS package in R/Bioconductor. Results: We find a borderline significant association between the mitochondrial variant rs28357980, localized to MT-ND2, and BMI (β = − 0.69, p = 0.056). This BMI association was confirmed on 1889 patients from FHS cohort (β = − 0.312, p = 0.047). Next, we searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in the genes SIRT3, ATP5B, CYCS, TFB2M and POLRMT. TFB2M is a mitochondrial transcription factor and together with TFAM creates a transcription promoter complex for the mitochondrial polymerase POLRMT. We have found an interaction between rs3021088 in MT-ND2 and rs6701836 in TFB2M leading to BMI decrease (inter_pval = 0.0241), while interaction of rs3021088 in MT-ND2 and rs41542013 in POLRMT led to BMI increase (inter_pval = 0.0004). The influence of these interactions on BMI was confirmed in external cohorts. Conclusions: Here, we have shown that variants in the mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.

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“…For example, conplastic rats where shown to have impaired glucose tolerance, while mice were more resistant to experimental autoimmune encephalomyelitis [28], had disrupted activity of the components of TCA cycle [29] or altered mitochondrial and cellular adaptation during aging [30]. Moreover, the mutation in MT-ND2 gene (C4738A) in mouse fibroblasts led to significantly higher mitochondrial complex I activity, enhanced ATP production, reduced ROS production with similar MT-ND2 protein expression levels [31]. A lot of studies have shown that even a point mutation in mitochondrial genome which was introduced onto another nuclear background led to severe mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Title: “Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients”

Ludwig-Słomczyńska

Seweryn

Kapusta

et al. 2018

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UM, KC, PG and ŁD gathered study cohort and phenotypic data; EWO and MTM supervised 22 cohort construction; AHLS and EP performed genotyping; AHLS, MTS and PK analyzed and 23 interpreted data; AHLS, MTS, PK and PPW wrote the paper; AHLS and PPW and guarantors 24 of this work. All authors contributed to critical revision of the manuscript and approved its 25 publication. Abstract 27Mitochondria are organelles whose main role is energy production and might influence obesity. 28They are the only organelles with their own genome. Here we have genotyped 435 patients with 29 type 1 diabetes using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed 30 mitoGWAS on BMI. We have analyzed additive interactions between mitochondrial and 31 nuclear variants in genes known to be associated with mitochondrial functioning 32 (MitoCarta2.0) and confirmed and refined the results on external cohorts -Framingham Heart 33 Study (FHS) and GTEx data. The linear mixed model analysis was performed using the 34 GENESIS package in R/Bioconductor We have found a nominal association between 35 rs28357980 localized to MT-ND2 and BMI (β=-0.69, p=0.056). This was confirmed on 1889 36 patients from FHS cohort (β =-0.312, p=0.047). Next, we have searched for additive 37interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with 38 variants in SIRT3, ATP5B, CYCS, TFB2M and POLRMT genes. TFB2M is a mitochondrial 39 transcription factor and together with TFAM creates transcription promoter complex for 40 mitochondrial polymerase POLRMT. We have found that the interaction between rs3021088 41 of MT-ND2 gene and rs6701836 in TFB2M has led to BMI decrease (inter_pval=0.0241), while 42 interaction of rs3021088in MT-ND2 and rs41542013 in POLRMT gene led to BMI increase 43 (inter_pval=0.0004). The influence of these interactions on BMI was confirmed on external 44 cohorts. Here, we have shown that variants in mitochondrial genome as well as additive 45 interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general 46 cohorts. 48Author summary: 49 Obesity is an epidemic of our times. It is known that it results from an imbalance between 50 energy intake and its expenditure, while mitochondria are organelles whose main role is energy 3 51 production. They are the only organelles that contain their own genome. Thus, we have 52 genotyped 435 patients with type 1 diabetes and looked on single mitochondrial variant 53 influence as well as on additive interactions between mitochondrial and nuclear variants which 54 might affect BMI. Our analysis has shown, that rs28357980 localized to MT-ND2 is associated 55 with BMI. Next, we looked whether variants in this gene, which builds complex I of the electron 56 transport chain, might interact with nuclear variants and together they modify obesity risk. We 57 focused mainly on mitochondrial biogenesis and found that interactions between variants in 58 TFB2M (rs6701836) or POLRMT (rs41542013) and MT-ND2 (rs3021088) affect patients 59 BMI. TFB2M is a mit...

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A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging

Cited by 13 publications

References 41 publications

Reduced Adolescent-Age Spatial Learning Ability Associated with Elevated Juvenile-Age Superoxide Levels in Complex I Mouse Mutants

Reduced Adolescent-Age Spatial Learning Ability Associated with Elevated Juvenile-Age Superoxide Levels in Complex I Mouse Mutants

Mitochondrial GWAS and association of nuclear – mitochondrial epistasis with BMI in T1DM patients

Title: “Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients”

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