scholarly journals Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

EMBO Reports ◽  
2021 ◽  
Author(s):  
Mara Mennuni ◽  
Roberta Filograna ◽  
Andrea Felser ◽  
Nina A Bonekamp ◽  
Patrick Giavalisco ◽  
...  
Keyword(s):  
Metabolic Resistance ◽  
Mitochondrial Transcription

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.

scholarly journals POLRMT mutations impair mitochondrial transcription causing neurological disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Monika Oláhová ◽  
Bradley Peter ◽  
Zsolt Szilagyi ◽  
Hector Diaz-Maldonado ◽  
Meenakshi Singh ◽  
...  
Keyword(s):  
Progressive External Ophthalmoplegia ◽  
Global Developmental Delay ◽  
Disease Mechanism ◽  
Mitochondrial Transcription ◽  
Functional Studies ◽  
Mtdna Deletions ◽  
Molecular Nature ◽  
Important Disease

AbstractWhile >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.

scholarly journals Quantitative proteomics revealed C6orf203/MTRES1 as a factor preventing stress-induced transcription deficiency in human mitochondria

2019 ◽  
Vol 47 (14) ◽  
pp. 7502-7517 ◽  
Author(s):  
Anna V Kotrys ◽  
Dominik Cysewski ◽  
Sylwia D Czarnomska ◽  
Zbigniew Pietras ◽  
Lukasz S Borowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Mitochondrial Gene ◽  
Binding Activity ◽  
Stress Conditions ◽  
Mitochondrial Rna ◽  
Mitochondrial Gene Expression ◽  
Compensatory Mechanisms ◽  
Temporary Reduction ◽  
Mitochondrial Transcription

AbstractMaintenance of mitochondrial gene expression is crucial for cellular homeostasis. Stress conditions may lead to a temporary reduction of mitochondrial genome copy number, raising the risk of insufficient expression of mitochondrial encoded genes. Little is known how compensatory mechanisms operate to maintain proper mitochondrial transcripts levels upon disturbed transcription and which proteins are involved in them. Here we performed a quantitative proteomic screen to search for proteins that sustain expression of mtDNA under stress conditions. Analysis of stress-induced changes of the human mitochondrial proteome led to the identification of several proteins with poorly defined functions among which we focused on C6orf203, which we named MTRES1 (Mitochondrial Transcription Rescue Factor 1). We found that the level of MTRES1 is elevated in cells under stress and we show that this upregulation of MTRES1 prevents mitochondrial transcript loss under perturbed mitochondrial gene expression. This protective effect depends on the RNA binding activity of MTRES1. Functional analysis revealed that MTRES1 associates with mitochondrial RNA polymerase POLRMT and acts by increasing mitochondrial transcription, without changing the stability of mitochondrial RNAs. We propose that MTRES1 is an example of a protein that protects the cell from mitochondrial RNA loss during stress.

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

scholarly journals Opening–closing dynamics of the mitochondrial transcription pre-initiation complex

2011 ◽  
Vol 40 (1) ◽  
pp. 371-380 ◽  
Author(s):  
Hajin Kim ◽  
Guo-Qing Tang ◽  
Smita S. Patel ◽  
Taekjip Ha
Keyword(s):  
Initiation Complex ◽  
Mitochondrial Transcription

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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