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

2018 ◽  
Author(s):  
Agnieszka H. Ludwig-Słomczyńska ◽  
Michał T. Seweryn ◽  
Przemysław Kapusta ◽  
Ewelina Pitera ◽  
Urszula Mantaj ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transcription Factor ◽  
Energy Production ◽  
Main Role ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Heart Study ◽  
Promoter Complex ◽  
Additive Interactions

AbstractMitochondria are organelles whose main role is energy production and might influence obesity. They are the only organelles with their own genome. Here we have genotyped 435 patients with type 1 diabetes using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We have analyzed additive interactions between mitochondrial and nuclear variants in genes known to be associated with mitochondrial functioning (MitoCarta2.0) and confirmed and refined the results on external cohorts - Framingham Heart Study (FHS) and GTEx data. The linear mixed model analysis was performed using the GENESIS package in R/Bioconductor We have found a nominal association between rs28357980 localized to MT-ND2 and BMI (β=−0.69, p=0.056). This was confirmed on 1889 patients from FHS cohort (β =−0.312, p=0.047). Next, we have searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in SIRT3, ATP5B, CYCS, TFB2M and POLRMT genes. TFB2M is a mitochondrial transcription factor and together with TFAM creates transcription promoter complex for mitochondrial polymerase POLRMT. We have found that the interaction between rs3021088 of MT-ND2 gene and rs6701836 in TFB2M has led to BMI decrease (inter_pval=0.0241), while interaction of rs3021088in MT-ND2 and rs41542013 in POLRMT gene led to BMI increase (inter_pval=0.0004). The influence of these interactions on BMI was confirmed on external cohorts. Here, we have shown that variants in mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.Author summaryObesity is an epidemic of our times. It is known that it results from an imbalance between energy intake and its expenditure, while mitochondria are organelles whose main role is energy production. They are the only organelles that contain their own genome. Thus, we have genotyped 435 patients with type 1 diabetes and looked on single mitochondrial variant influence as well as on additive interactions between mitochondrial and nuclear variants which might affect BMI. Our analysis has shown, that rs28357980 localized to MT-ND2 is associated with BMI. Next, we looked whether variants in this gene, which builds complex I of the electron transport chain, might interact with nuclear variants and together they modify obesity risk. We focused mainly on mitochondrial biogenesis and found that interactions between variants in TFB2M (rs6701836) or POLRMT (rs41542013) and MT-ND2 (rs3021088) affect patients BMI. TFB2M is a mitochondrial transcription factor which, together with TFAM, creates transcription promoter complex and enables transcription by mitochondrial polymerase POLRMT. The obtained results were also confirmed and refined on external cohorts - Framingham Heart Study (FHS) and GTEx data. Thus, we have shown that variations in mitochondrial genome and its interactions with nuclear variants might have an influence on BMI.

scholarly journals Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zheng Fu ◽  
Joseph W. Dean ◽  
Lifeng Xiong ◽  
Michael W. Dougherty ◽  
Kristen N. Oliff ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Intestine ◽  
Th17 Cells ◽  
Tissue Remodeling ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Tuft Cell ◽  
Mitochondrial Transcription Factor A

AbstractRORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

Structural models of mammalian mitochondrial transcription factor B2

2015 ◽  
Vol 1849 (8) ◽  
pp. 987-1002 ◽  
Author(s):  
Ibrahim M. Moustafa ◽  
Akira Uchida ◽  
Yao Wang ◽  
Neela Yennawar ◽  
Craig E. Cameron
Keyword(s):  
Transcription Factor ◽  
Structural Models ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor

141 Mitochondrial transcription factor a mitochondrial DNA repair

Mitochondrion ◽  
2010 ◽  
Vol 10 (2) ◽  
pp. 240
Author(s):  
Deborah L. Croteau ◽  
Anne-Cécile V. Bayne ◽  
Chandrika Canugovi ◽  
Scott Maynard ◽  
Nadja de Souza-Pinto ◽  
...  
Keyword(s):  
Dna Repair ◽  
Transcription Factor ◽  
Mitochondrial Dna ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Dna Repair ◽  
Mitochondrial Transcription Factor A

Selected Contribution: Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle

2001 ◽  
Vol 90 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Joe W. Gordon ◽  
Arne A. Rungi ◽  
Hidetoshi Inagaki ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Regulatory Protein ◽  
Mrna Levels ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Mitochondrial Transcript

Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.

A human mitochondrial transcriptional activator can functionally replace a yeast mitochondrial HMG-box protein both in vivo and in vitro

1993 ◽  
Vol 13 (3) ◽  
pp. 1951-1961
Author(s):  
M A Parisi ◽  
B Xu ◽  
D A Clayton
Keyword(s):  
Transcription Factor ◽  
Mitochondrial Dna ◽  
Nuclear Gene ◽  
Transcriptional Activator ◽  
Yeast Mitochondria ◽  
Yeast Protein ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A

Human mitochondrial transcription factor A is a 25-kDa protein that binds immediately upstream of the two major mitochondrial promoters, thereby leading to correct and efficient initiation of transcription. Although the nature of yeast mitochondrial promoters is significantly different from that of human promoters, a potential functional homolog of the human transcriptional activator protein has been previously identified in yeast mitochondria. The importance of the yeast protein in yeast mitochondrial DNA function has been shown by inactivation of its nuclear gene (ABF2) in Saccharomyces cerevisiae cells resulting in loss of mitochondrial DNA. We report here that the nuclear gene for human mitochondrial transcription factor A can be stably expressed in yeast cells devoid of the yeast homolog protein. The human protein is imported efficiently into yeast mitochondria, is processed correctly, and rescues the loss-of-mitochondrial DNA phenotype in a yeast abf2 strain, thus functionally substituting for the yeast protein. Both human and yeast proteins affect yeast mitochondrial transcription initiation in vitro, suggesting that the two proteins may have a common role in this fundamental process.

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