Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation

Cardamone, Maria Dafne; Tanasă, Bogdan; Cederquist, Carly; Huang, Jiawen; Mahdaviani, Kiana; Li, Wenbo; Rosenfeld, Michael G.; Liesa, Marc; Perissi, Valentina

doi:10.1016/j.molcel.2018.01.037

Cited by 92 publications

(104 citation statements)

References 88 publications

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“…A number of recent studies suggest that alterations of the epigenome, driven by transcription factors and coregulators, influence adipose tissue plasticity in mice and humans ( Rosen, 2016 , Toubal et al., 2013b ). Among the candidate coregulators, subunits of the HDAC3 corepressor complex (reviewed in Treuter et al., 2017 ) have emerged as important regulators of the adipose tissue phenotype in obesity ( Cardamone et al., 2014 , Cardamone et al., 2018 , Cederquist et al., 2016 , Fan et al., 2016 , Fang et al., 2011 , Li et al., 2011 , Rohm et al., 2013 , Toubal et al., 2013a ). Although apparently different aspects of the respective KO phenotypes were characterized, these studies collectively imply that subunit-selective alterations of diverse repression pathways potentially trigger transcriptional reprogramming of adipocytes, which may also affect adipose tissue plasticity favoring hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation

et al. 2018

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SummaryHypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. This phenotype is driven by HIF1A activation that orchestrates inadequate WAT remodeling and disrupts mitochondrial activity, which can be reversed by pharmacological or genetic HIF1A inhibition. Correlation analysis of gene expression in human adipose tissue reveals a negative relationship between GPS2 and HIF1A, adipocyte hypertrophy, and insulin resistance. We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status in mice and humans.

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Section: Introductionmentioning

confidence: 99%

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation

et al. 2018

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“…Their transcriptional activity is in fact directly regulated by the MT functional status through regulated MT-to-nucleus translocation [30]. This feedback transmits mitochondrial signals such as transcription factors leading to changes in nuclear gene expression and a reconfiguration of metabolism to accommodate cells to MT status changes.…”

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confidence: 99%

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

et al. 2020

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Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune-mediated diseases. They exert immunoregulatory and tissue-restoring effects. MSC-mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose-dependent MitoT from mitochondria-labeled MSCs mainly to CD4 + T cells, rather than CD8 + T cells or CD19 + B cells. Artificial transfer of isolated MSCderived mitochondria increases the expression of mRNA transcripts involved in T-cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFb1, leading to an increase in a highly suppressive CD25 + FoxP3 + population. In a GVHD mouse model, transplantation of MitoT-induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4 + , CD8 + , and IFN-c + expressing cell infiltration. These findings point to a unique CD4 + T-cell reprogramming mechanism with pre-clinical proof-of-concept data that pave the way for the exploration of organelle-based therapies in immune diseases.

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“…2017 42:625-639; Cell Tissue Res. 2017 367: [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Therefore, we propose a hypothetical working model in Fig.…”

Section: Supplemental Discussionmentioning

confidence: 99%

“…ETC complex genes contain mitochondrial-encoded (MEGs) and nuclear-encoded mitochondrial genes (NEMGs). Many studies have examined mechanisms underlying transcriptional regulation of these genes 13,14,15,16,17,18,19,20 . However, the role of regulation of protein expression of NEMGs and MEGs in cardiac disease has received little attention until recently.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-574 Regulates FAM210A Expression and Influences Pathological Cardiac Remodeling

Subbaiah

Jiang

et al. 2020

Preprint

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Aberrant synthesis of mitochondrial proteins impairs cardiac function and causes heart disease. However, the mechanism of regulation of mitochondria encoded protein expression during cardiac disease remains underexplored. Here, we have shown that multiple pathogenic cardiac stressors induce the expression of miR-574 guide and passenger strands (miR-574-5p/3p) in both humans and mice. miR-574 knockout mice exhibit severe cardiac disorder under heart disease-triggering stresses. miR-574-5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults.Transcriptome analysis of miR-574-null hearts uncovers FAM210A as a common target mRNA for both strands of miR-574. The interactome capture and translational state analyses suggest that FAM210A interacts with mitochondrial translation factors and regulates the protein expression of mitochondrial encoded electron transport chain genes. Using a human cardiomyocyte cell culture system, we discover that miR-574 regulates FAM210A expression and modulates mitochondrial encoded protein expression, which influences cardiac remodeling in heart failure.Abbreviations of key terms: ACM, adult cardiomyocytes; CF, cardiac fibroblasts; CM, cardiomyocytes; ETC, electron transport chain; FAM210A, family with sequence similarity 210 member A; HF, heart failure; ISO, isoproterenol; MEG, mitochondrial encoded gene; MI, myocardial infarction; NEMG, nuclear-encoded mitochondrial gene; RBP, RNA-binding protein; RISC, RNA-induced silencing complex; TAC, transverse aortic constriction; UTR, untranslated region Results Cardiac stress induces miR-574-5p and miR-574-3p in human and mouse heartsFrom data mining of unbiased screening data from four laboratories, the guide strand miR-574-5p has been identified as a miRNA that is robustly induced in the heart in response to pathological cardiac remodeling, which included the cardiac tissues of patients during the initial stages following MI onset 33 , a mouse model of left coronary artery occlusion-derived MI 24 , and aged murine hearts ( Fig. 1a) 26 . On the other hand, the passenger strand miR-574-3p is increased in the human hearts after MI and more remarkably induced by exercise training in murine hearts 34 . The cardiac functions of complementary strands of miR-574-5p and miR-574-3p remain unknown. miR-574 is conserved in 43 animal species (10 primates and 33 mammals, UCSC Genome Browser). In mammals, miR-574 is located in intron 1 of the host gene FAM114A1 (Family with sequence similarity 114 member A1) ( Fig. 1b). We confirmed that both miR-574-5p and miR-574-3p were significantly induced in heart tissues of chronic HF patients, with the expression level of miR-574-5p even higher than that of miR-574-3p (Fig. 1c). Northern blot analysis showed that both miR-574-5p and miR-574-3p were expressed in the normal murine heart ( Supplementary Fig. 1a). miR-574-5p and miR-574-3p were both significantly induced in isoproterenol (ISO)-or transverse aortic constriction (TAC)-treated mouse hearts, compar...

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Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation

Cited by 92 publications

References 88 publications

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

MicroRNA-574 Regulates FAM210A Expression and Influences Pathological Cardiac Remodeling

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