Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival (original) (raw)
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The FASEB Journal, 2015
Conventional T (Tcon) cells and Foxp3 + Tregulatory (Treg) cells are thought to have differing metabolic requirements, but little is known of mitochondrial functions within these cell populations in vivo. In murine studies, we found that activation of both Tcon and Treg cells led to myocyte enhancer factor 2 (Mef2)-induced expression of genes important to oxidative phosphorylation (OXPHOS). Inhibition of OXPHOS impaired both Tcon and Treg cell function compared to wild-type cells but disproportionally affected Treg cells. Deletion of Pgc1a or Sirt3, which are key regulators of OXPHOS, abrogated Treg-dependent suppressive function and impaired allograft survival. Mef2 is inhibited by histone/ protein deacetylase-9 (Hdac9), and Hdac9 deletion increased Treg suppressive function. Hdac9 2/2 Treg showed increased expression of Pgc1a and Sirt3, and improved mitochondrial respiration, compared to wild-type Treg cells. Our data show that key OXPHOS regulators are required for optimal Treg function and Treg-dependent allograft acceptance. These findings provide a novel approach to increase Treg function and give insights into the fundamental mechanisms by which mitochondrial energy metabolism regulates immune cell functions in vivo.-Beier, U.
2022
A decline in mitochondrial activity has been linked to T cell dysfunction and the progression of a variety of diseases. It is unclear whether the mitochondrial function in regulatory T cells (Tregs) determines effector T cell fate decisions and regulates steady-state inflammation. We show that loss of Mitochondrial Transcription Factor A in Foxp3+ Tregs (TFAM cKO) affects the cellular and transcriptional dynamics of CD4+ T cells, resulting in disproportional cellular heterogeneity and prevalence of pathogenic CD4+ T cell subsets. Failure to modulate CD4+ T cell responses results in systemic inflammation, immunological aging, and shortened lifespans in TFAM cKO mice. Furthermore, we found that TFAM heterozygous (Het) mice with 50% allelic restoration had a progressive decrease in physiological, cognitive, and neuromuscular activity starting at 8 months, implying that the TFAM Het mouse model has the potential to be used for in-depth research on age-related inflammatory diseases. Over...
Scientific Reports, 2021
The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during short-term ex vivo expansion enhances the stability of iTreg FOXP3 expression and suppressive function in vitro and in vivo, and further that a key mechanism of action is MSC mitochondrial (mt) transfer via tunneling nanotubules (TNT). MSC mt transfer is driven by mitochondrial metabolic function (CD39/CD73 signaling) in proliferating iTreg and promotes iTreg expression of FOXP3 stabilizing factors BACH2 and SENP3. These results elucidate cellular and molecular mechanisms underlying human MSC mt transfer to proliferating cells. MSC mt transfer stabilizes FOXP3 expression in iTregs, thereby enhancing and sustaining their suppressive function in inflammatory conditions in vitro and in vivo.
Cell death & disease, 2018
While aberrant cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of cancer cell homeostasis, playing a dual role in survival/death response to metabolic stress and cancer therapeutics. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage. Here, we show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support mitochondrial metabolism. Using FoxO3A cancer cells generated with the CRISPR/Cas9 genome editing system and reconstituted with FoxO3A mutants being imp...
Diabetology & Metabolic Syndrome, 2011
Background: FOXC2 has lately been implicated in diabetes and obesity as well as mitochondrial function and biogenesis and also as a regulator of mtTFA/Tfam. In this study, the expression of FOXC2 and selected genes involved in mitochondrial function and biogenesis in healthy subjects and in a matched cohort with type 2 diabetes patients before and after treatment with rosiglitazone was determined. Quantitative real time PCR was used to analyze both RNA and DNA from biopsies from subcutaneous adipose tissue. Methods: Blood samples and subcutaneous abdominal fat biopsies were collected from 12 T2D patients, of which 11 concluded the study, pre-treatment and 90 days after initiation of rosiglitazone treatment, and from 19 healthy control subjects on the first and only visit from healthy subjects. Clinical parameters were measured on the blood samples. RNA and DNA were prepared from the fat biopsies and gene expression was measured with real time PCR. Results: The expression level of genes in the mitochondrial respiratory complexes I -IV were significantly downregulated in the diabetic patients and restored in response to rosiglitazone treatment. Rosiglitazone treatment also increased the relative number of mitochondria in diabetic patients compared with controls. Furthermore, the transcription factors FOXC2 and mtTFA/Tfam displayed a response pattern identical to the mitochondrial genes. Conclusions: FOXC2, mtTFA/Tfam and subunits of the respiratory complexes I -IV show equivalent regulation in gene expression levels in response to TZD treatment. This, together with the knowledge that FOXC2 has a regulatory function of mtTFA/Tfam and mitochondrial biogenesis, suggests that FOXC2 has a possible functional role in the TZD activated mitochondrial response.
F1000 - Post-publication peer review of the biomedical literature, 2000
It is widely appreciated that T cells increase glycolytic flux during activation, however the role of mitochondrial flux is unclear. Here we have shown that mitochondrial metabolism, in the absence of glucose metabolism, was sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs −/− mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, however Uqcrfs1 −/− T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1 −/− T cells were not lacking bioenergetically, but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through production of complex III ROS.
Immunity, 2013
It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs À/À mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigenspecific expansion of T cells in vivo, but Uqcrfs1 À/À T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1 À/À T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS.
International Journal of Biological Sciences, 2008
Cellular longevity is a complex process relevant to age-related diseases including but not limited to chronic illness such as diabetes and metabolic syndromes. Two gene families have been shown to play a role in the genetic regulation of longevity; the Sirtuin and FOXO families. It is also established that nuclear Sirtuins interact with and under specific cellular conditions regulate the activity of FOXO gene family proteins. Thus, we hypothesize that a mitochondrial Sirtuin (SIRT3) might also interact with and regulate the activity of the FOXO proteins. To address this we used HCT116 cells overexpressing either wild-type or a catalytically inactive dominant negative SIRT3. For the first time we establish that FOXO3a is also a mitochondrial protein and forms a physical interaction with SIRT3 in mitochondria. Overexpression of a wild-type SIRT3 gene increase FOXO3a DNA-binding activity as well as FOXO3a dependent gene expression. Biochemical analysis of HCT116 cells over expressing the deacetylation mutant, as compared to wild-type SIRT3 gene, demonstrated an overall oxidized intracellular environment, as monitored by increase in intracellular superoxide and oxidized glutathione levels. As such, we propose that SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway.
Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis
Science, 2021
Metabolic pathway regulates cell fate Lineage-specific regulators direct cell fate decisions, but the precise mechanisms are not well known. Using an in vivo chemical suppressor screen of a bloodless zebrafish mutant, Rossmann et al. show that the lineage-specific chromatin factor tif1γ directly regulates mitochondrial genes to drive red blood cell differentiation. Loss of tif1γ reduces coenzyme Q synthesis and function, impeding mitochondrial respiration and leading to epigenetic alterations and repression of erythropoiesis. The loss of blood in the mutant fish can be rescued by the addition of coenzyme Q. This work establishes a mechanism by which a chromatin factor tunes a metabolic pathway in a tissue-specific manner. Science , this issue p. 716