Stress and glucocorticoid receptor regulation of mitochondrial gene expression

Glucocorticoids have long been recognized for their role in regulating the availability of energetic resources, particularly during stress. Furthermore, bidirectional connections between glucocorticoids and the physiology and function of mitochondria have been discovered over the years. However, the precise mechanisms by which glucocorticoids act on mitochondria have only recently been explored. Glucocorticoids appear to regulate mitochondrial transcription via activation of glucocorticoid receptors (GRs) with elevated circulating glucocorticoid levels following stress. While several mechanistic questions remain, GR and other nuclear transcription factors appear to have the capacity to substantially alter mitochondrial transcript abundance. The regulation of mitochondrial transcripts by stress and glucocorticoids will likely prove functionally relevant in many stress-sensitive tissues including the brain.

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Mitochondrial Glucocorticoid Receptors and Their Actions

International Journal of Molecular Sciences ◽

10.3390/ijms22116054 ◽

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

Nucleic Acids Research ◽

10.1093/nar/gkz542 ◽

2019 ◽

Vol 47 (14) ◽

pp. 7502-7517 ◽

Cited By ~ 6

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.

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Inhibition of mitochondrial gene expression by antisense RNA of mitochondrial transcription factor A (mtTFA)

IUBMB Life ◽

10.1080/15216549800202962 ◽

1998 ◽

Vol 45 (3) ◽

pp. 567-573 ◽

Cited By ~ 1

Author(s):

Hidetoshi Inagaki ◽

Shigetomo Kitano ◽

Kong Hua Lin ◽

Sumio Maeda ◽

Takao Saito

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Antisense Rna ◽

Mitochondrial Gene ◽

Mitochondrial Gene Expression ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Mitochondrial Transcription Factor A

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Skeletal muscle bioenergetic health and function in people living with HIV: association with glucose tolerance and alcohol use

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00197.2021 ◽

2021 ◽

Author(s):

Danielle E. Levitt ◽

Tekeda F Ferguson ◽

Stefany DePrato Primeaux ◽

Jeanette A Zavala ◽

Jameel Ahmed ◽

...

Keyword(s):

Gene Expression ◽

Alcohol Use ◽

Glucose Tolerance ◽

Mitochondrial Gene ◽

Proton Leak ◽

Mitochondrial Gene Expression ◽

Mitochondrial Volume ◽

And Function ◽

The Relationship

At-risk alcohol use is prevalent and increases dysglycemia among people living with human immunodeficiency virus (PLWH). Skeletal muscle (SKM) bioenergetic dysregulation is implicated in dysglycemia and type 2 diabetes. The objective of this study was to determine the relationship between at-risk alcohol, glucose tolerance, and SKM bioenergetic function in PLWH. Thirty-five PLWH (11 females, 24 males, age: 53±9 yrs, body mass index: 29.0±6.6 kg/m2) with elevated fasting glucose enrolled in the ALIVE-Ex study provided medical history and alcohol use information (Alcohol Use Disorders Identification Test, AUDIT), then underwent an oral glucose tolerance test (OGTT) and SKM biopsy. Bioenergetic health and function and mitochondrial volume were measured in isolated myoblasts. Mitochondrial gene expression was measured in SKM. Linear regression adjusting for age, sex, and smoking was performed to examine the relationship between glucose tolerance (2-h glucose post-OGTT), AUDIT, and their interaction with each outcome measure. Negative indicators of bioenergetic health were significantly (p<0.05) greater with higher 2-h glucose (proton leak) and AUDIT (proton leak, non-mitochondrial oxygen consumption, and bioenergetic health index). Mitochondrial volume was increased with the interaction of higher 2-h glucose and AUDIT. Mitochondrial gene expression decreased with higher 2-h glucose (TFAM, PGC1B, PPARG, MFN1), AUDIT (MFN1, DRP1, MFF), and their interaction (PPARG, PPARD, MFF). Decreased expression of mitochondrial genes were coupled with increased mitochondrial volume and decreased bioenergetic health in SKM of PLWH with higher AUDIT and 2-h glucose. We hypothesize these mechanisms reflect poorer mitochondrial health and may precede overt SKM bioenergetic dysregulation observed in type 2 diabetes.

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A Role of P300 in Post-natal Cardiac Mitochondrial Gene Expression and Function

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2006.08.094 ◽

2006 ◽

Vol 12 (8) ◽

pp. S162-S163

Author(s):

Yasuaki Nakagawa ◽

Koichiro Kuwahara ◽

Masaki Harada ◽

Genzo Takemura ◽

Masaharu Akao ◽

...

Keyword(s):

Gene Expression ◽

Mitochondrial Gene ◽

Mitochondrial Gene Expression ◽

And Function

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Recombinant Mitochondrial Transcription Factor A with N-terminal Mitochondrial Transduction Domain Increases Respiration and Mitochondrial Gene Expression in G11778A Leber's Hereditary Optic Neuropathy Cybrid Cells

Nature Precedings ◽

10.1038/npre.2008.2084.1 ◽

2008 ◽

Author(s):

Shilpa Iyer ◽

Ravindar Thomas ◽

Francisco Portell ◽

Lisa Dunahm ◽

Caitlin Quigley ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Optic Neuropathy ◽

Mitochondrial Gene ◽

Mitochondrial Gene Expression ◽

Leber's Hereditary Optic Neuropathy ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Mitochondrial Transcription Factor A ◽

Hereditary Optic Neuropathy

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Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression

Mitochondrion ◽

10.1016/j.mito.2009.01.012 ◽

2009 ◽

Vol 9 (3) ◽

pp. 196-203 ◽

Cited By ~ 39

Author(s):

Shilpa Iyer ◽

Ravindar R. Thomas ◽

Francisco R. Portell ◽

Lisa D. Dunham ◽

Caitlin K. Quigley ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Mitochondrial Gene ◽

Mitochondrial Gene Expression ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Mitochondrial Transcription Factor A

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Sirtuin-1 isoforms differentially regulate mitochondrial function

Innovation in Aging ◽

10.1093/geroni/igab046.2512 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 671-671

Author(s):

Xiaomin Zhang ◽

Fathima Ameer ◽

Jasmine Crane ◽

Gohar Azhar ◽

Jeanne Wei

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Mitochondrial Gene ◽

Intracellular Localization ◽

Sirtuin 1 ◽

Protein Domain ◽

Mitochondrial Gene Expression ◽

Age Related ◽

And Function ◽

Mitofusin 1

Abstract Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. Alternatively spliced isoforms may lose part of the protein domain and have different intracellular localization as well as distinct functions. The main form of the SIRT1 (SIRT1v1) protein contains 11 exons. We have identified two new isoforms, SIRT1v2 (lost 2 exons), and SIRT1v3 (lost 3 exons), but their effect on mitochondrial gene expression has not been reported. To study the effect of the three SIRT1 isoforms on mitochondrial gene expression and function, neuronal cells were transfected with SIRT1 isoforms v1, v2 or v3 plasmids, respectively. Gene expression was measured by quantitative reverse transcription PCR (RT-qPCR). Our data showed SIRT1 isoforms v1, v2 and v3 differentially regulated PCG-1alpha and PCG-1beta, which are the upstream regulators of mitochondrial structure and function. SIRT1v1 upregulated mitofusin-1 (MFN1), the mitochondrial dynamin-like GTPase (OPA1) gene, and the transcription factor A mitochondrial (TFAM) gene. In contrast, the SIRT1-v2 isoform repressed the MFN1, MFN2, and TFAM genes, while the SIRT1-v3 isoform repressed the MFN1 gene. In addition, the three SIRT1 isoforms differentially affected the mitochondrial respiratory complex I genes, including NDUFAB1, NDUFS1, NDUFV1, NDUFV2. The data indicates that SIRT1 regulates mitochondrial biogenesis and function through a signaling pathway involving PGC-1alpha, PCG-1beta, mitofusin 1 and 2, OPA1, and TFAM genes. Taken together, alternative splicing generated three SIRT1 isoform proteins with diverse functions. Age-related changes in the alternative splicing events are likely to impact sirtuin-regulated cellular functions and signaling pathways in aging and senescence.

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