Effect of deletion of liver Mitofusin 1 (Mfn1) on energy metabolism in high fat diet fed mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE74888 | GEO | 2016/03/31
SECONDARY ACCESSION(S): PRJNA301732
REPOSITORIES: GEO
Similar Datasets
Project description:Microarray analysis of the livers from Mfn1 WT and Mfn1 LKO mice fed with high fat diet. We hypothesised that deletion of Mfn1 will lead reduced mitochondrial fusion thus leading to an increase in the number of smaller but higher functional mitochondria and increase in mitochondrial proteins. Total RNA obtained from isolated livers from a six hours fasted Mfn1 WT or Mfn1 LKO mice.
2016-03-31 | E-GEOD-74888 | biostudies-arrayexpress
Project description:Mitofusin 1 (Mfn1) is a transmembrane GTPase protein implicated in mitochondrial fusion. To investigate the potential role of Mfn1 in energy balance and metabolism control we generated mice lacking Mfn1 specifically in hypothalamic POMC neurons (POMCMfn1KO). We used microarrays to determine gene expression changes resulting from deletion of Mfn1 in POMC neurons under fed and fasting conditions
2017-06-27 | GSE81993 | GEO
Project description:MFN2 is a mitochondrial outer membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2 (which cause Charcot-Marie-Tooth disease type 2A) primarily affect the nervous system. We generated a transgenic mouse model of CMT2A which developed severe early-onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria labeled for degradation. Mutant MFN2R94Q had a dominant negative effect on mitochondrial fusion if MFN1 was absent or at low levels, as in neurons. Finally we found that augmenting the level of MFN1 in the nervous system in vivo led to rescue of all phenotypes in mutant MFN2R94Q expressing mice. These data demonstrate that the MFN1:MFN2 ratio is a key determinant of tissue specificity in CMT2A, and indicates that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.
2019-04-03 | GSE116863 | GEO
Project description:The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mtDNA content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, induced impaired mitochondrial morphology and networking fragmentation, and impaired decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Indeed, pharmacologic mitofusin agonists rescued islet mtDNA depletion due to mitofusin deficiency independent of changes on mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.
2022-02-16 | GSE194204 | GEO
Project description:Objective: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells. Methods: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA. Results: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings. Conclusions: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.
2023-06-01 | GSE232502 | GEO
Project description:If the function of the nuclear receptor PPARa is well-known during a prolongated fasting, its hepatic biological function during feeding and refeeding conditions still needs to be investigated. Moreover, in vivo data collected so far on PPARa function during fasting were obtained using the total Ppara KO transgenic mouse model. To identify genes whose expression is under the strict dependence of hepatic PPARa activity, we generated a new mouse strain of PPARa-specific deletion in hepatocyte (albumin-Cre+/- Pparaflox/flox or LKO) and we compared them to total Ppara KO (KO), wild-type (WT) and liver WT (albumin-Cre-/- Pparaflox/flox or LWT) mice under three nutritional challenges. We used microarrays to detail the global programme of gene expression in liver of Ppara LKO, LWT, Ppara KO and WT male mice fed ad libitum, fasted for 24 hours and refed. There are 52 liver samples, each from an individual mouse. The samples are from Ppara liver KO (LKO), Ppara KO (KO), wild-type (WT) and liver WT (LWT) male mice of 8 week-old from the same genetic background (C57Bl/6J) fed ad libitum, fasted for 24 hours, fasted for 24 hours and then refed 24 hours more with glucose added in water (200g/l). In fed condition (Fed), n= 3 mice for LKO, LWT genotypes, n= 5 for KO and n= 4 fot WT; in fasting condition (Fas), n=5 for LKO, LWT and WT genotypes and n= 3 for KO; in refeeding condition (Ref), n= 5 for LKO, KO and WT genotypes and n= 4 for LWT. All mice were sacrified at ZT14.
2016-02-20 | E-GEOD-73299 | biostudies-arrayexpress
Project description:Cellular senescence is a therapy endpoint in melanoma, and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and an enhanced mitochondrial energy metabolism supports resistance to therapy in melanoma. In a previous report we showed that in melanoma, senescence induced by the DNA methylating agent temozolomide, increases fusion proteins mitofusins 1 and 2. Silencing Mfn1 or Mfn2 expression reduced interleukin-6 secretion by senescent cells. Here we expanded these observations evaluating the secretome of senescent melanoma cells using shotgun proteomics, and explored the impact of silencing Mfn1 on the SASP. A significant increase in proteins reported to reduce the immune response towards the tumor was found in the media of senescent cells. The secretion of several of these immunomodulatory proteins was affected by Mfn1 silencing, among them was galectin-9. In agreement, tumors lacking mitofusin 1 responded better to treatment with the methylating agent dacarbazine, tumor size was reduced and a higher immune cell infiltration was detected in the tumor. Our results highlight mitochondrial dynamic proteins as potential pharmacological targets to modulate the SASP in the context of melanoma treatment.
2024-01-26 | PXD043779 | Pride
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease, where lung function decline is gradual and the overall prognosis of patients with IPF is poor with a median survival after diagnosis of approximately 3.8 years. Growing evidence points to the fundamental role for the mitochondrion in alveolar type 2 (AEC2) cell dysfunction in the pathogenesis of IPF. Additionally, single-cell RNA sequencing (RNA-Seq) recently identified MFN2 mRNA as significantly upregulated in AEC2 cells from patients with IPF, suggesting a role for mitochondrial fusion in AEC2 cells and the development of IPF. To investigate the roles of mitofusin 1 (MFN1) and mitofusin 2 (MFN2) of AEC2 cells in the pathogenesis of pulmonary fibrosis, we utilized genetically modified mice harboring MFN1 and/or MFN2 flanked by two loxP sites, and crossed them with Sftpc-CreERT2 mice, in which the AEC2 cell specific Sftpc-promoter drives the expression of tamoxifen-responsive CreERT2. Using this approach, we were able to selectively delete MFN1, MFN2 and both MFN1 and MFN2 together in AEC2 cells of the lung. Profoundly, in the absence of both mitofusins in AEC2 cells, we observe significant morbidity and mortality associated with disordered mitochondrial dynamics, failure of surfactant lipid production and the development of spontaneous pulmonary fibrosis, reminiscent of usual interstitial pneumonitis observed in the lungs of patients with IPF. Furthermore, we showed that mice with MFN1 or MFN2 deletion in AEC2 cells would have deteriorated bleomycin-induced pulmonary fibrosis. The results together confirmed the critical roles of MFN1 and MFN2 in AEC2 cells in protecting the lung from fibrotic process.
2019-06-07 | GSE115730 | GEO
Project description:CR6-interacting factor-1 (CRIF1) interacting with large mitoribosome subunits is essential for the maturation and insertion of oxidative phosphorylation (OxPhos) polypeptides into the mitochondrial inner membrane. Recently, it has reported that the genetic ablation of Crif1 in a tissue-specific manner results in mitochondrial stress response (MSR) including mitochondrial unfolded protein response (UPRmt). In this study, we aim to obtain a comprehensive understanding of systemic energy metabolism in response to hepatic mitochondrial dysfunction. Through the liver-specific Crif1 deficient mice (LKO), we explore the adaptive response not only in the liver but also in inguinal white adipose tissue (iWAT). Moreover, RNA sequencing in liver, iWAT, skeletal muscle, and hypothalamus suggest that hepatic mitochondrial dysfunction enhance metabolic pathways, including glycolysis, fatty acid elongation and degradation, and 1C metabolism in liver and insulin signaling in iWAT. RNA sequencing also suggests that hepato-mitokines, GDF15 and FGF21 are highly increased in liver of LKO mice. To identify the role of hepato-mitokines, we generate double knockout mice (LKO/Gdf15-/- and LKO/Fgf21-/-), suggesting that GDF15 is responsible for the regulation of the body and fat mass and FGF21 has a critical role for the insulin sensitivity and energy expenditure in this mice.
2021-03-10 | GSE149553 | GEO
Project description:Here we show that synthesis of the mitochondrial phospholipid cardiolipin is an indispensable driver of thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response by overexpressing cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency diminishes mitochondrial uncoupling in brown and beige adipocytes and elicits a nuclear transcriptional response through ER stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake and renders animals strikingly insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin is a powerful regulator of organismal energy homeostasis through thermogenic fat bioenergetics.
2018-07-19 | GSE110297 | GEO