SIRT1 regulates enhanced mitochondrial respiration and leukemogenicity in CML stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA530246 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8833070_1.fastq.gz | Fastqsanger.gz | |||
| SRR8833070_2.fastq.gz | Fastqsanger.gz | |||
| SRR8833071_1.fastq.gz | Fastqsanger.gz | |||
| SRR8833071_2.fastq.gz | Fastqsanger.gz | |||
| SRR8833064_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL tyrosine kinase. We have shown that the SIRT1 deacetylase is overexpressed in CML LSC, and may contribute to their maintenance. Here, using genetic deletion of SIRT1 in transgenic CML mice, we definitively demonstrate that SIRT1 is required for leukemia development, and reveal its critical role in mediating increased mitochondrial respiration in CML LSC.
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Project description:Leukemia stem cells (LSC) are not eradicated in chronic myeloid leukemia (CML) patients responding to tyrosine kinase inhibitor treatment. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) maintenance. Here, we examined leukemia-induced alterations in mesenchymal progenitor populations using a murine CML model. 6C3+ stroma-forming progenitors were increased in CML BM, and demonstrated enhanced LSC but reduced HSC support compared to their normal counterparts. CML 6C3 cells showed enhanced TNFa-related gene signatures, and upregulated CXCL1 expression. TNFα signaling contributed to expansion and increased CXCL1 expression by 6C3 cells in CML BM. The CXCL1 receptor CXCR2 was upregulated in in LSC, and CXCR2 inhibition significantly reduced LSC growth both in vitro and in vivo. In conclusion, TNFα-induced alterations in stromal progenitors in CML BM result in enhanced CML LSC growth via CXCL1-CXCR2 signaling. Targeting this axis represents a novel therapeutic strategy to inhibit BM niche-protected LSC.
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Project description:Description
Mitochondrial respiration in mammalian cells not only generates ATP to meet their own energy needs but also couples with biosynthetic pathways to produce metabolites that can be exported to support neighboring cells. However, how defects in mitochondrial respiration influence these biosynthetic and exporting pathways remains poorly understood. In this study we used targeted-metabolomics to investigate how inhibition of mitochondrial respiration influences the intracellular and extracellular metabolome.
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Project description:Background: Sarcopenia contributes to all-cause mortality in the elderly; however, there is no specific treatment. Mesenchymal stromal cells (MSCs) ameliorate age-related muscle loss and dysfunction, and are potential therapeutic candidates for sarcopenia. However, their activity is easily affected by the surrounding environment and they are prone to replicative senescence during in vitro culture. Therefore, a drug that delays aging and enhances its function is required. Here, we investigated whether nicotinamide adenine dinucleotide (NAD+) pretreatment enhances the therapeutic efficacy of MSCs on skeletal muscle atrophy and its underlying mechanism in a D-gal-induced aging model. Methods: C57BL/6J mice and C2C12-differentiated myotubes exposed to D-gal were used to explore the effects of MSCs/NAD+-MSCs on muscle atrophy. MSCs/NAD+-MSCs were injected into the skeletal muscles of the hind limbs every 7 days for six cycles. Treadmill running and grip strength tests were used to evaluate the muscle strength. Muscle weight and fiber cross-sectional area (CSA) were used to measure muscle mass. Multiomics analysis of quadriceps and NAD+-pretreated MSCs (NAD+-MSCs), western blotting of muscle atrophy signaling, including Atrogin 1 and MuRF1, the mitochondrial complex, fatty acid oxidation indicators, and Seahorse analysis were performed to explore the underlying mechanisms. Results: MSCs increased grip strength (p=0.0005), running endurance (p=0.0006), and muscle mass (p=0.0165 for tibialis anterior (TA) muscle, p=0.0049 for soleus (SO) muscle) in D-gal-treated mice, with elevated muscle fiber CSA (p<0.0001), and reduced Atrogin1 (p=0.0242) and MuRF1 expression (p=0.0009). NAD+ pretreatment increased the effect of MSCs on muscle atrophy (p=0.0009 for grip strength, p=0.0169 for running endurance, p=0.0506 for TA muscle weight, p=0.0238 for SO muscle weight, p=0.0002 for muscle fiber CSA, p=0.0005 for Atrogin1 expression and p=0.0223 for MuRF1 expression). MSCs/NAD+-MSCs activated the SIRT1/PGC-1α signaling, enhanced mitochondrial function and fatty acid oxidation in D-gal-induced mice and C2C12 myotubes. SIRT1 knockdown weakened the beneficial effects of MSCs/NAD+-MSCs on muscle atrophy. RNA-seq of MSCs/NAD+-MSCs and proteomic analysis of their supernatants revealed that NAD+ enhanced the therapeutic effect of MSCs by promoting NAMPT secretion. Conclusions: NAD+ enhances the therapeutic effect of MSCs on age-related muscle atrophy by promoting NAMPT secretion, which acts on the SIRT1 signaling pathway, and improves mitochondrial function and fatty acid oxidation in skeletal muscles. This study provides new insights and a theoretical basis for the clinical treatment of sarcopenia.
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Project description:Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production
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Project description:Metabolism of chimeric antigen receptor (CAR) T cells is emerging as an important area to improve CAR-T cell therapy in cancer treatment. Mitochondrial respiration is essential for survival and function of CAR-T cells, but developing strategies to specifically enhance mitochondrial respiration has been challenging. Here we identify MCJ/DnaJC15, an endogenous negative regulator of mitochondrial Complex I, as a metabolic target to enhance mitochondrial respiration in CD8 CAR-T cells. Loss of MCJ in CD8 CAR-T cells increases their in vitro and in vivo efficacy against mouse B cell leukemias. MCJ deficiency in TCR- specific CD8 cells also increases their efficacy against solid tumors in vivo. Furthermore, we reveal that human CD8 cells express MCJ and that silencing MCJ expression increases mitochondrial metabolism and anti-tumor activity of human CAR-T cells. Thus, we demonstrate the unique therapeutic potential of targeting MCJ to enhance the metabolism and efficacy of adoptive T cell therapies.
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Project description:CD8 T cell proliferation and memory formation are linked to changes in metabolism, which has important implications for improving CD8 T cell fitness in therapies against chronic infections and cancer. The mitochondrial electron transport chain (ETC) is essential for antigen-specific CD8 T cell proliferation. Mitochondrial ETC function is linked to the generation of ATP, production of metabolites to sustain proliferation, and signaling molecules including reactive oxygen species (ROS), which determine T cell function and fate. However, it is not fully understood which mitochondrial ETC functions are necessary for CD8 T cell proliferation in vivo. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production, and superoxide production, decreases CD8 T cell proliferation and memory formation. CD8 T cells lacking functional mitochondrial complex III also exhibit an exhausted-like phenotype following acute stimulation. The expression of Ciona intestinalis alternative oxidase (AOX), which accepts electrons from coenzyme Q, thus compensating for the loss of mitochondrial complex III function without generating ROS or proton pumping, restores respiration, proliferation and largely prevents the exhausted phenotype in vitro and in vivo. However, AOX did not sustain memory CD8 T cells, suggesting mitochondrial complex III ROS is necessary for optimal memory formation. These findings demonstrate that the primary function of the mitochondrial ETC in CD8 T cells is enabling respiration to sustain proliferation and memory formation as well as to prevent an exhausted phenotype.
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