Abstract 16765: Cyclophilin-D: A Regulator of Mitochondrial Gene Expression

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Raúl J Gazmuri
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Electron Transport ◽  
Respiratory Chain ◽  
Post Infection ◽  
Mitochondrial Gene ◽  
Cellular Respiration ◽  
Mitochondrial Gene Expression ◽  
Cyclophilin D ◽  
Heavy Strand

Background: Cyclophilin-D (Cyp-D) is a peptidyl-prolyl isomerase resident in the mitochondrial matrix; and like other cyclophilins it can catalyze conformational changes of proteins. Cyp-D is best known for its role in lowering the threshold for opening of the mitochondrial permeability transition pore. However, a serendipitous observation by us, whereby Cyp-D silencing halted cell proliferation, and reports by others that Cyp-D could interact with nuclear transcription factors that have translocated to mitochondria, prompted us to hypothesize that Cyp-D could interact with native mitochondrial transcription factors (mTFs; TFB1M, TFB2M, and TFAM) and therefore be a key regulator of mitochondrial gene expression. Given that all 13 mitochondrial-encoded proteins are components of respiratory chain complexes, our hypothesis would support a central role of Cyp-D in cellular respiration. Methods and Results: We first analyzed the interaction of Cyp-D with mTFs by co-immunoprecipitation (co-IP) and reverse co-IP after transfection of constructs expressing FLAG-tagged Cyp-D and V5-tagged mTFs in HEK 293T cells, showing specific interactions of Cyp-D with TFB1M and with TFB2M but not with TFAM. We then quantitated by real time qPCR mitochondrial-encoded respiratory chain transcripts in HEK 293T cells at day 8 post-infection with lentiviruses encoding shRNA against Cyp-D, showing striking reductions in transcripts ND1, COX1, and ATP6 (initiated from the heavy strand promoter 2) but not in transcript ND6 (initiated from the light strand promoter). Finally, we measured cellular oxygen consumption, also on post-infection day 8, and found it reduced without improvement after uncoupling of electron transport from ATP synthesis with FCCP, consistent with the aforementioned reductions in mitochondrial transcripts of electron transport complexes. At the same time, mitochondrial mass, expression of nuclear genes, and cell viability were all preserved. Conclusion: In HEK 293 T cells, Cyp-D is required for mitochondrial gene expression modulating transcription possibly through the heavy strand promoter 2 suggesting a novel Cyp-D function as regulator of oxidative phosphorylation and thus of the fundamental process of cellular respiration.

Cyclophilin-D: A Novel regulator of mitochondrial gene expression

Mitochondrion ◽  
2015 ◽  
Vol 24 ◽  
pp. S24-S25
Author(s):  
Jeejabai Radhakrishnan ◽  
Raúl J. Gazmuri
Keyword(s):  
Gene Expression ◽  
Mitochondrial Gene ◽  
Mitochondrial Gene Expression ◽  
Cyclophilin D

scholarly journals Inactivation of the mitochondrial protease Afg3l2 results in severely diminished respiratory chain activity and widespread defects in mitochondrial gene expression

2020 ◽  
Author(s):  
Gautam Pareek ◽  
Leo J. Pallanck
Keyword(s):  
Gene Expression ◽  
Respiratory Chain ◽  
Ribosome Biogenesis ◽  
Mitochondrial Gene ◽  
Mitochondrial Proteins ◽  
Null Alleles ◽  
Mitochondrial Gene Expression ◽  
Genetic Approach ◽  
Mitochondrial Ribosome ◽  
Partial Inactivation

AbstractThe m-AAA proteases plays a critical role in the proteostasis of the inner mitochondrial membrane proteins, and mutations in the genes encoding these proteases cause severe incurable neurological diseases. To further explore the biological role of the m-AAA proteases and the pathological consequences of their deficiency, we used a genetic approach in the fruit fly Drosophila melanogaster to inactivate the ATPase family gene 3-like 2 (AFG3L2) gene, which encodes a component of the m-AAA proteases. We found that null alleles of Drosophila AFG3L2 die early in development, but partial inactivation of AFG3L2 using RNAi extended viability to the late pupal and adult stages of development. Flies with partial inactivation of Afg3l2 exhibited marked behavioral defects, neurodegeneration, mitochondrial morphological alterations, and diminished respiratory chain (RC) activity. Further work revealed that reduced RC activity was a consequence of widespread defects in mitochondrial gene expression, including diminished mitochondrial transcription, translation and impaired mitochondrial ribosome biogenesis. These defects were accompanied by the compensatory activation of the mitochondrial unfolded protein response (mito-UPR) and accumulation of unfolded mitochondrial proteins, including proteins involved in transcription. Overexpression of the mito-UPR components partially rescued the Afg3l2-deficient phenotypes, indicating that sequestration of essential components of the mitochondrial gene expression into aggregates partly accounts for these defects. However, Afg3l2 also co-sediments with the mitochondrial ribosome biogenesis machinery, suggesting an additional novel role for Afg3l2 in ribosome biogenesis. Our work suggests that strategies designed to modify mitochondrial stress pathways and mitochondrial gene expression could be therapeutic in the diseases caused by mutations in AFG3L2.Author SummaryMitochondria produce virtually all of the cellular energy through the actions of the respiratory chain (RC) complexes. However, both the assembly of the RC complexes, and their biological functions come at a cost. Biogenesis of the RC complexes depends on the coordinated expression of nuclear and mitochondrially encoded subunits and an imbalance in this process can cause protein aggregation. Moreover, the RC complexes produce highly damaging reactive oxygen species as a side product of their activity. The Mitochondrial AAA+ family of proteases are believed to provide the first line of defense against these insults. The importance of this protease family is best exemplified by the severe neurodegenerative diseases that are caused by mutations in their respective genes. To better understand the biological roles of the AAA+ proteases, and the physiological consequences of their inactivation we used a genetic approach in Drosophila to study the Afg3l2 AAA+ protease. Unexpectedly, we found that Afg3l2 deficiency profoundly impaired mitochondrial gene expression, including transcription, translation and ribosome biogenesis. These phenotypes were accompanied by accumulation of insoluble mitochondrial proteins, and compensatory activation of mito-UPR and autophagy. Our work indicates Afg3l2 plays critical roles in degrading unfolded mitochondrial proteins and regulating mitochondrial gene expression.

scholarly journals A Human Mitochondrial Transcription Factor Is Related to RNA Adenine Methyltransferases and Binds S-Adenosylmethionine

2002 ◽  
Vol 22 (4) ◽  
pp. 1116-1125 ◽  
Author(s):  
Vicki McCulloch ◽  
Bonnie L. Seidel-Rogol ◽  
Gerald S. Shadel
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Mitochondrial Gene ◽  
Factor H ◽  
Model Systems ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor

ABSTRACT A critical step toward understanding mitochondrial genetics and its impact on human disease is to identify and characterize the full complement of nucleus-encoded factors required for mitochondrial gene expression and mitochondrial DNA (mtDNA) replication. Two factors required for transcription initiation from a human mitochondrial promoter are h-mtRNA polymerase and the DNA binding transcription factor, h-mtTFA. However, based on studies in model systems, the existence of a second human mitochondrial transcription factor has been postulated. Here we report the isolation of a cDNA encoding h-mtTFB, the human homolog of Saccharomyces cerevisiae mitochondrial transcription factor B (sc-mtTFB) and the first metazoan member of this class of transcription factors to which a gene has been assigned. Recombinant h-mtTFB is capable of binding mtDNA in a non-sequence-specific fashion and activates transcription from the human mitochondrial light-strand promoter in the presence of h-mtTFA in vitro. Remarkably, h-mtTFB and its fungal homologs are related in primary sequence to a superfamily of N6 adenine RNA methyltransferases. This observation, coupled with the ability of recombinant h-mtTFB to bind S-adenosylmethionine in vitro, suggests that a structural, and perhaps functional, relationship exists between this class of transcription factors and this family of RNA modification enzymes and that h-mtTFB may perform dual functions during mitochondrial gene expression.

Cyclophilin‐D: a resident regulator of mitochondrial gene expression

2015 ◽  
Vol 29 (7) ◽  
pp. 2734-2748 ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Stanley Bazarek ◽  
Bala Chandran ◽  
Raúl J. Gazmuri
Keyword(s):  
Gene Expression ◽  
Mitochondrial Gene ◽  
Mitochondrial Gene Expression ◽  
Cyclophilin D

scholarly journals Mitochondrial Glucocorticoid Receptors and Their Actions

2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptors ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Ros Generation ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Energy Metabolism ◽  
Bcl2 Family ◽  
Cellular Processes ◽  
Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

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