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USP28-regulated mitochondrial homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts [ChIP-seq]

ABSTRACT: The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. PPARα-/- in the db/db background mice were constructed to check the mechanism of USP28 in vivo. Inducible cardiac-specific deletion of Mfn2 in the db/db background mice was utilized to evaluate USP28-mediated cardioprotection. chromatin immunoprecipitation (ChIP) assays revealed that PPARα promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244905 | GEO | 2023/10/15

REPOSITORIES: GEO

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USP28 Serves as A Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart [RNA-seq]

Project description:The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. cardiac USP28 deficient diabetic mice showed cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared to their controls. Conversely, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Mechanistically, USP28 directly interacted with peroxisome proliferator-activated receptor α (PPARα), deubiquitinating and stabilizing PPARα (Lys152) to promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects.

2023-10-15 | GSE244904 | GEO

RNA-seq of overgrown interscapular adipose tissue with biallelic MFN2 mutations

Project description:Mitofusin 2 (MFN2) mutations previously associated with axonal neuropathy have recently been found in patients with upper body overgrowth of adipose tissue. RNA-seq was performed on two of these patients with biallelic MFN2 mutations. The transcriptome demonstrated increased mitochondrial stress signaling, increased cell survive and decreased cell death signatures, and increased protein synthesis.

2017-04-12 | GSE97156 | GEO

DIAPH1-MFN2 interaction regulates mitochondria-sarcoplasmic reticulum contact and modulates ischemic/hypoxic stress

Project description:Inter-organelle contact and communication between mitochondria (Mito) and endoplasmic reticulum (ER), also known as sarcoplasmic reticulum (SR) in cardiomyocytes (CM), play vital roles in the maintenance of Mito and SR properties and cellular homeostasis. Here, we tested the hypothesis that the formin, Diaphanous-1 (DIAPH1), which regulates actin dynamics and signal transduction, contributes to these processes. Mice bearing CM-specific deletion of Diaph1 displayed reduced injury and superior functional recovery after the induction of cardiac ischemia and reperfusion (I/R). Studies in DIAPH1-silenced human induced pluripotent stem cell-derived CMs (HiPSC-CMs) and murine hearts devoid of CM-Diaph1 revealed that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to regulate Mito-SR contact, Mito turnover, mitophagy, and oxidative stress. Ischemic murine hearts and human heart biopsies revealed more robust DIAPH1-MFN2 interaction vs. that observed in non-ischemic hearts. Solution structure studies affirm this interaction and reveal strong pH-dependent interaction between the Diaphanous Inhibitory Domain (DID) and the cytosolic GTPase domain of MFN2. In HiPSC-CMs, introduction of synthetic linkers, which reduce the Mito-SR distance, mitigated the cardioprotective benefits of Diaph1 deletion. Finally, DIAPH1 binding to the cytoplasmic domain of receptor for advanced glycation endproduct (RAGE) supports signal transduction and contributes to I/R injury in the heart; in HiPSC-CMs, small molecule antagonism of RAGE-DIAPH1 reduced DIAPH1-MFN2 interaction and increased Mito-SR distance. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of Mito-SR contact networks that control responses to ischemic stress. Targeting pathways that regulate DIAPH1-MFN2 may facilitate recovery from cardiac ischemic injury.

2022-09-28 | GSE214149 | GEO

Effect of Usp28 knockout and re-consitution of wildtype or monomeric Usp28 on gene expression in hepatocellular carcinoma cells

Project description:Usp28-KO HLF cell lines were generated by CRISPR-Cas9. Usp28-KO cells expressing Usp28-WT, Usp28-Mono or a control vector were established by lentiviral transduction.

2023-09-30 | GSE213892 | GEO

Dual regulation of Fbw7 function and oncogenic transformation by Usp28

Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation. RNAseq experiments of E13.5 murine embryonic fibroblasts (MEFs) derived from animals in which Usp28 was either deleted (-/-), wildtype (+/+) or heterozygous (+/-). In a first set of experiments immortalized MEFs of all three genotypes were analysed in biological triplicates. In a second set of experiments immortalized and Ras transformed MEFs of all three genotypes and MEFs which overexpress USP28 (+/+/+) where sequenced in duplicates.

2015-05-01 | E-GEOD-59354 | biostudies-arrayexpress

RNA sequencing of pancreatic islets from WT, Mfn1-/-, Mfn2-/- and Mfn1/2-/- mice

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

Dual regulation of Fbw7 function and oncogenic transformation by Usp28

2015-05-01 | GSE59354 | GEO

Combined RNAinterfering and gene therapy targeting MFN2 for the treatment of Charcot-Marie-Tooth type 2A

Project description:Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy with impact on the entire nervous system. To date, no curative treatment is available. In the paper we propose a novel therapeutic strategy tailored to correct the root genetic defect of CMT2A. In our approach, while mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing a cDNA encoding a functional MFN2, modified to be resistant to RNAi. This strategy allows proper MFN2 molecular correction in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs via adenoassociated virus 9 (AAV9) in newborn mice. To identify the therapeutic molecular mechanisms and the pathway that are modulated, we have compared the bulk RNA expression profile of spinal cord from one month old wild type (WT) mice and MitoCharc1 transgenic mice (B6;D2-Tg(Eno2-MFN2*R94Q)L51Ugfm/J) which encode the mutant human MFN2*R94Q under the neuron specific rat enolase (Eno2) promoter, as potential mouse model to test the therapeutic approach. We performed gene expression profiling analysis using data (RNA-seq) obtained from 4 wild type mice and 8 MitoCharch1 transgenic mice at one time point.

2023-11-29 | GSE201264 | GEO

Effect of knockout (KO) of Usp28 on gene expression in embryonic stem cells(ESCs) cultured under 2iL condition

Project description:For validating the role Usp28 in regulating mouse ESC self-renewal, sgRNAs were designed to generate Usp28 KO cell lines. We then performed gene expression profiling analysis using data obtained from RNA-seq control (CTL) and Usp28 KO ESCs.

2023-05-01 | GSE229112 | GEO

RNAseq from Mfn1/2 knockout MEFs with adipogenic differentiation

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

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