Restoring mitochondrial quantity and quality to reverse warburg effect and drive neuroblastoma differentiation
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ABSTRACT:
PROVIDER: PRJNA1216192 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR32137176_1.fastq.gz | Fastqsanger.gz | |||
| SRR32137176_2.fastq.gz | Fastqsanger.gz | |||
| SRR32137177_1.fastq.gz | Fastqsanger.gz | |||
| SRR32137177_2.fastq.gz | Fastqsanger.gz | |||
| SRR32137178_1.fastq.gz | Fastqsanger.gz |
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Project description:Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation
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Project description:Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
2025-01-29 | GSE288099 | GEO
Project description:Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
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Project description:Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
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Project description:Two Neolithic Y. pestis genomes from Warburg
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Project description:BackgroundDegenerative diseases are a major public health concern for the aging population and mesenchymal stem cells (MSCs) have great potential for treating many of these diseases. However, the quantity and quality of MSCs declines with aging, limiting the potential efficacy of autologous MSCs for treating the elderly population.MethodsHuman bone marrow (BM)-derived MSCs from young and elderly donors were obtained and characterized using standard cell surface marker criteria (CD73, CD90, CD105) as recommended by the International Society for Cellular Therapy (ISCT). The elderly MSC population was isolated into four subpopulations based on size and stage-specific embryonic antigen-4 (SSEA-4) expression using fluorescence-activated cell sorting (FACS), and subpopulations were compared to the unfractionated young and elderly MSCs using assays that evaluate MSC proliferation, quality, morphology, intracellular reactive oxygen species, β-galactosidase expression, and adenosine triphosphate (ATP) content.ResultsThe ISCT-recommended cell surface markers failed to detect any differences between young and elderly MSCs. Here, we report that elderly MSCs were larger in size and displayed substantially higher concentrations of intracellular reactive oxygen species and β-galactosidase expression and lower amounts of ATP and SSEA-4 expression. Based on these findings, cell size and SSEA-4 expression were used to separate the elderly MSCs into four subpopulations by FACS. The original populations (young and elderly MSCs), as well as the four subpopulations, were then characterized before and after culture on tissue culture plastic and BM-derived extracellular matrix (BM-ECM). The small SSEA-4-positive subpopulation representing ~ 8% of the original elderly MSC population exhibited a "youthful" phenotype that was similar to that of young MSCs. The biological activity of this elderly subpopulation was inhibited by senescence-associated factors produced by the unfractionated parent population. After these "youthful" cells were isolated and expanded (three passages) on a "young microenvironment" (i.e., BM-ECM produced by BM cells from young donors), the number of cells increased ≈ 17,000-fold to 3 × 109 cells and retained their "youthful" phenotype.ConclusionsThese results suggest that it is feasible to obtain large numbers of high-quality autologous MSCs from the elderly population and establish personal stem cell banks that will allow serial infusions of "rejuvenated" MSCs for treating age-related diseases.
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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.
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