Role of mitochondrial fission-related genes in mitochondrial morphology and energy metabolism in mouse embryonic stem cells
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ABSTRACT:
PROVIDER: PRJNA626620 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11575426_1.fastq.gz | Fastqsanger.gz | |||
| SRR11575426_2.fastq.gz | Fastqsanger.gz | |||
| SRR11575427_1.fastq.gz | Fastqsanger.gz | |||
| SRR11575427_2.fastq.gz | Fastqsanger.gz | |||
| SRR11575428_1.fastq.gz | Fastqsanger.gz |
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Project description:Here we aimed to investigate the function of mitochondrial fission genes in embryonic stem cells (ESCs). Homozygous knockout ESC lines, namely, Fis1-/- , Mff-/- , and Dnm1l-/- ESCs, were generated using the CRISPR-Cas9 system. After then, we analyzed whole genome expression profile for characterizing cellular responses by incomplete mitochondrial fission.
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Project description:Mitochondria, the major organelles that produce energy for cell survival and function, dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. The details of the underlying mechanism of mitochondrial dynamics have not yet been elucidated. Here, we aimed to investigate the function of mitochondrial fission genes in embryonic stem cells (ESCs). To this end, we generated homozygous knockout ESC lines, namely, Fis1-/-, Mff-/-, and Dnm1l-/- ESCs, using the CRISPR-Cas9 system. Interestingly, the Fis1-/-, Mff-/-, and Dnm1l-/- ESCs showed normal morphology, self-renewal, and the ability to differentiate into all three germ layers in vitro. However, transmission electron microscopy showed a significant increase in the cytoplasm to nucleus ratio and mitochondrial elongation in Dnm1l-/- ESCs, which was due to incomplete fission. To assess the change in metabolic energy, we analyzed oxidative phosphorylation (OXPHOS), glycolysis, and the intracellular ATP concentration. The ESC knockout lines showed an increase in OXPHOS, decrease in glycolysis, and an increase in intracellular ATP concentration, which was related to mitochondrial elongation. In particular, the Dnm1l knockout most significantly affected mitochondrial morphology, energy metabolism, and ATP production in ESCs. Furthermore, RNA sequencing and gene ontology analysis showed that the differentially expressed genes in Mff-/- ESCs were distinct from those in Dnm1l-/- or Fis1-/- ESCs. In total, five metabolism-related genes, namely, Aass, Cdo1, Cyp2b23, Nt5e, and Pck2, were expressed in all three knockout ESC lines, and three of them were associated with regulation of ATP generation.
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Project description:Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.
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Project description:The detachment of epithelial cells, but not cancer cells, causes anoikis due to reduced energy production. Invasive tumor cells generate three splice variants of the metastasis gene osteopontin. The cancer-specific form osteopontin-c supports anchorage-independence through inducing oxidoreductases and upregulating intermediates/enzymes in the hexose monophosphate shunt, glutathione cycle, glycolysis, glycerol phosphate shuttle, and mitochondrial respiratory chain. Osteopontin-c signaling upregulates glutathione (consistent with the induction of the enzyme GPX-4), glutamine and glutamate (which can feed into the tricarboxylic acid cycle). Consecutively, the cellular ATP levels are elevated. The elevated creatine may be synthesized from serine via glycine and also supports the energy metabolism by increasing the formation of ATP. Metabolic probing with N-acetyl-L-cysteine, L-glutamate, or glycerol identified differentially regulated pathway components, with mitochondrial activity being redox dependent and the creatine pathway depending on glutamine. The effects are consistent with a stimulation of the energy metabolism that supports anti-anoikis. Our findings imply a synergism in cancer cells between osteopontin-a, which increases the cellular glucose levels, and osteopontin-c, which utilizes this glucose to generate energy. mRNA profiles of MCF-7 cells transfected with osteopontin-a, osteopontin-c and vector control were generated by RNA-Seq, in triplicate, by Illumina HiSeq.
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Project description:Atherosclerosis (AS) is one of the most common diseases in middle-age and elderly population. Lipid metabolism disorder induced foaming of vascular smooth muscle cell (VSMC) is an important pathological process of AS. Mitochondria plays an important role in lipids metabolism. While it is not known whether regulating mitochondrial function can protect ox-LDL induced VSMC foaming via metabolic reprogramming. With ox-LDL induced mouse model of VSMC injury, the injury effect of ox-LDL and the protective effect of mdivi-1, the mitochondrial fission inhibitor on mitochondrial morphology and function of VSMC, and the formation of lipid droplet were observed. With metabonomics and proteomics techniques, the main lipid metabolites and regulation proteins were identified. The results showed that Ox-LDL induced a significant mitochondrial fission and fragmentation of VSMC, and mitochondrial function disorder along with lipid deposition and foaming. Mdivi-1 significantly antagonized the damage effect of ox-LDL on mitochondrial morphology and function of VSMC, and blocked the lipid deposition. Metabonomics analysis found 848 different metabolites between ox-LDL and mdivi-1 treatment group, in which the lipid metabolites were the main, and heptadecanoic acid, palmitoleic acid and myristic acid were the critical metabolites changed most. Proteomics results showed that there were 125 differential expressed proteins between ox-LDL and mdivi-1 treatment, acetyl -CoA carboxylase1 and fatty acid synthase were the main differential expressed proteins. This study suggest that Mitochondrial fission plays an important role in VSMC lipid deposition and foaming. Inhibition of mitochondrial fission may effectively fight against ox-LDL induced lipid deposition and foaming of VSMC via improving mitochondrial function and metabolic reprogramming. This finding provides a new insight for prevention and treatment of AS.
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