MITOCHONDRIAL ANTIOXIDANTS ABATE SARS-COV-2 LETHALITY IN MICE
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246312 | GEO | 2024/07/31
REPOSITORIES: GEO
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Project description:SARS-CoV-2 polypeptides bind mitochondrial proteins, and the virus inhibits oxidative phosphorylation (OXPHOS) nuclear DNA (nDNA) gene transcription by blocking coordinately expressed genes of modular components of the OXPHOS holoenzymes. While initial nasopharyngeal infection is associated with the down regulation of OXPHOS genes, at death lung OXPHOS is up regulated. By contrast, heart, kidney, and liver nDNA gene expression remains suppressed, likely contributing to mortality. The virus also induces miR-2392 which inhibits mitochondrial DNA (mtDNA) transcription and the translation of mitochondrial cytosolic mRNAs. This concerted inhibition of OXPHOS activates HIF-1α inducing a pseudo-hypoxic state favoring viral biogenesis. We interrogated the effects of SARS-CoV-2 infection by infecting BALB/c and C57BL/6 mice with the mouse-adapted SARS-CoV-2 MA10 virus and analyzed their lung transcripts at day 4 post infection.
2022-12-27 | GSE221510 | GEO
Project description:The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1 and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glut1), lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase-1 (PDK1), were observed in areas of lung consolidation filled with infiltrating monocytes/macrophages. Upregulation of these HIF-1α target proteins was accompanied by a rise in glycolysis as measured by extracellular acidification rate (ECAR) in lung homogenates. A concomitant marginal reduction in mitochondrial respiration was also observed as seen by a partial loss of oxygen consumption rates (OCR) in both coupled and uncoupled states of respiration in isolated mitochondrial fractions of SARS-CoV-2 infected hamster lungs. Proteomics analysis revealed specific deficits in the mitochondrial ATP synthase (Atp5a1) within complex V and in the ATP/ADP translocase (Slc25a4). The activation of HIF-1 in inflammatory macrophages may also drive proinflammatory cytokines production, complement activation, and oxidative stress in infected lungs. Together, these findings support a role for HIF-1 as a central mediator of the metabolic reprogramming, inflammation, and mitochondrial dysfunction associated with COVID-19 disease.
2023-03-10 | PXD036862 | Pride
Project description:Regulatory B cells (Bregs) are immune cells that constrain the immune response and restrict inflammation via their expression of interleukin (IL)-10. However, the molecular mechanisms underlying Breg differentiation and IL-10 secretion remain unclear. Previous data suggest that cellular metabolism determines both the fate and function of these cells. Here, we suggest an essential role for mitochondrial oxidative phosphorylation (OXPHOS) in the regulation of IL-10 in these Bregs. We found that IL-10+ B cells from IL-10-green fluorescent protein-expressing mice had higher oxygen consumption rate than IL-10- B cells. In addition, inhibition of OXPHOS decreased the expression of IL-10 in B cells. Further, suppression of OXPHOS diminished the expression of surface markers for Bregs and impaired their therapeutic effects in dextran sulfate sodium-induced colitis. Mechanistically, mitochondrial OXPHOS was found to regulate the transcription factor HIF-1α through the extracellular signal-related kinase pathway. Taken together, this study reveals a strong correlation between mitochondrial OXPHOS and Breg phenotype/function, indicating OXPHOS as a therapeutic target in autoimmune diseases driven by Breg dysfunction.
2022-07-31 | GSE181765 | GEO
Project description:Tumor cells without mitochondrial DNA (mtDNA) reconstitute oxidative phosphorylation (OXPHOS) by acquiring host mitochondria from stromal cells, but the reasons why functional respiration is crucial for tumorigenesis remain unclear. To address this issue, we used time-resolved analysis of the initial stages of tumor formation by cells devoid of mtDNA and genetic manipulations of components of OXPHOS. We show that pyrimidine biosynthesis, supported by respiration-linked dihydroorotate dehydrogenase (DHODH), is strictly required to overcome cell cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis.
2018-10-01 | E-MTAB-6150 | biostudies-arrayexpress
Project description:We investigated the contentious role of mitochondrial reactive oxygen species (ROS) on mitochondrial DNA (mtDNA) quality and quantity in female reproductive aging. By conditionally knocking out the Sod2 gene in female mouse germline, we observed increased mitochondrial ROS and decreased oocyte quality, primarily due to impacts on OXPHOS complex II and mtDNA encoded mRNA levels. Interestingly, we found no increased mtDNA mutations, but alterations in mtDNA quantity, indicating the susceptibility of mtDNA to the mitochondrial ROS during reproductive aging. Notably, when we further decreased the basal level of mtDNA quantity by deactivating the mtSSB protein in Sod2 conditional knockout females, we observed an exacerbation of reproductive aging effects. This highlights the crucial role of mtDNA quantity in mitigating the impact of oxidative stress on fertility.
2024-09-09 | GSE251734 | GEO
Project description:<p> Human disorders of mitochondrial oxidative phosphorylation (OXPHOS) represent a devastating collection of inherited diseases. These disorders impact at least 1:5000 live births, and are characterized by multi-organ system involvement. They are characterized by remarkable locus heterogeneity, with mutations in the mtDNA as well as in over 77 nuclear genes identified to date. It is estimated that additional genes may be mutated in these disorders. </p> <p>To discover the genetic causes of mitochondrial OXPHOS diseases, we performed targeted, deep sequencing of the entire mitochondrial genome (mtDNA) and the coding exons of over 1000 nuclear genes encoding the mitochondrial proteome. We applied this 'MitoExome' sequencing to 124 unrelated patients with a wide range of OXPHOS disease presentations from the Massachusetts General Hospital Mitochondrial Disorders Clinic. </p> <p>The 2.3Mb targeted region was captured by hybrid selection and Illumina sequenced with paired 76bp reads. The total set of 1605 targeted nuclear genes included 1013 genes with strong evidence of mitochondrial localization from the MitoCarta database, 377 genes with weaker evidence of mitochondrial localization from the MitoP2 database and other sources, and 215 genes known to cause other inborn errors of metabolism. Approximately 88% of targeted bases were well-covered (>20X), with mean 200X coverage per targeted base. </p>
| phs000339 | dbGaP
Project description:Background: The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the MELAS syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. Objective: To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. Methods: Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. Results and Interpretation: Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1α (HIF-1α)/HIF-1β complex, nuclear factor Y (NF-Y) and CREB-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome. Peripheral blood samples were collected from ten A3243G MELAS patients and twenty age- and sex-matched healthy controls (2 controls for each patient). The patient cohort consisted of 4 females and 6 males, mean±s.e.m. age was 44.1±11.9 years (range: 22–63 years), mean±s.e.m. age at disease onset was 27.1±4.9 years (range: 13–55 years), mean±s.e.m. disease duration was 19.0±4.7 years (range: 4–43 years), and disease severity measured by the ‘Newcastle Mitochondrial Disease Adult Scale’ (NMDAS) 8 ranging from 0.0 (no symptoms) to 1.0 (maximum score) was 0.26±0.05 (range: 0.02–0.54).
2011-01-24 | E-GEOD-14882 | biostudies-arrayexpress
Project description:Defining mechanism(s) that maintain tissue stem quiescence is important for improving tissue regeneration, cell therapies, aging, and cancer. We report here that genetic ablation of Id2 in adult hematopoietic stem cells (HSCs) promotes increased HSC activation and differentiation, which results in HSC exhaustion and bone marrow failure over time. Id2Δ/Δ HSCs show increased HSC cycling, reactive oxygen species (ROS) production, mitochondrial activation, and DNA damage supporting the conclusion that Id2Δ/Δ HSCs are less quiescent. Mechanistically, HIF-1α expression is decreased in Id2Δ/Δ HSCs, and stabilization of HIF-1α in Id2Δ/Δ HSCs restores HSC quiescence and rescues HSC exhaustion. ID2 promotes HIF-1α expression by binding to the Von Hippel-Lindau (VHL) protein and interfering with proteasomal degradation of HIF-1α. HIF-1α promotes Id2 expression and enforces a positive feedback loop between ID2 and HIF-1α to maintain HSC quiescence. Thus, sustained ID2 expression could protect HSCs during stress, and improve HSC expansion for gene editing and cell therapies.
2022-05-31 | GSE203076 | GEO
Project description:Defining mechanism(s) that maintain tissue stem quiescence is important for improving tissue regeneration, cell therapies, aging, and cancer. We report here that genetic ablation of Id2 in adult hematopoietic stem cells (HSCs) promotes increased HSC activation and differentiation, which results in HSC exhaustion and bone marrow failure over time. Id2Δ/Δ HSCs show increased cycling, reactive oxygen species (ROS) production, mitochondrial activation, ATP production, and DNA damage compared to Id2+/+ HSCs, supporting the conclusion that Id2Δ/Δ HSCs are less quiescent. Mechanistically, HIF-1α expression is decreased in Id2Δ/Δ HSCs, and stabilization of HIF-1α in Id2Δ/Δ HSCs restores HSC quiescence and rescues HSC exhaustion. ID2 promotes HIF-1α expression by binding to the Von Hippel-Lindau (VHL) protein and interfering with proteasomal degradation of HIF-1α. HIF-1α promotes Id2 expression and enforces a positive feedback loop between ID2 and HIF-1α to maintain HSC quiescence. Thus, sustained ID2 expression could protect HSCs during stress, and improve HSC expansion for gene editing and cell therapies.
2022-05-31 | GSE205102 | GEO
Project description:Mitochondrial dysfunction causes oxidative stress and cardiomyopathy. Oxidative stress also is a side effect of dideoxynucleoside antiretrovirals (NRTI) and NRTI-induced cardiomyopathy. We show here that treatment with the NRTI AZT (1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione) modulates cardiac gene expression epigenetically through production of mitochondrially-derived reactive oxygen species (ROS). Transgenic mice with ubitquitous expression of mitochondrially-targeted catalase (MCAT) and C57BL/6 wild-type mice littermates (WT) were administered AZT (p.o., 0.22 mg/d; 35 days), and cardiac DNA and mRNA were isolated. In AZT-treated WT, 95 cardiac genes were differentially expressed compared to vehicle-treated WTs. When MCAT mice were treated with AZT, each of those 95 genes reverted to the pattern of vehicle-treated WTs. In AZT-treated WT hearts, Mthfr (5,10-methylenetetrahydrofolate reductase; a critical enzyme in synthesis of methionine cycle intermediates including S-adenosylmethionine (SAM)), was overexpressed. AZT caused hypermethylation (47%) and hypomethylation (53%) of differentially methylated DNA regions in WT cardiac DNA. AZT-treated MCAT heart DNA exhibited greater hypermethylation (91%) and less hypomethylation (9%) compared to vehicle-treated controls. Results show that mitochondrially-derived oxidative stress in the heart that is caused by AZT hinders cardiac DNA methylation, alters cardiac gene expression, and promotes characteristic pathophysiological changes of cardiomyopathy. This mechanism for NRTI toxicity offers insight into long-term side effects from these commonly used antiviral agents.
2016-05-23 | GSE54895 | GEO