Revealing the essential functions of mitochondrial NADPH and NADK2 for cell growth and proliferation
揭示线粒体 NADPH 和 NADK2 对细胞生长和增殖的基本功能
基本信息
- 批准号:10364228
- 负责人:
- 金额:$ 32.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdenineAffectAnabolismAntioxidantsBiochemicalBiologyBiomassCell ProliferationCellsCellular Metabolic ProcessCoupledDataDevelopmentDiseaseDrug Metabolic DetoxicationEnergy SupplyEnzymesExhibitsFutureGlucoseGlutamineGoalsGrowthHealthHealth BenefitHomeostasisHumanHuman Cell LineHypoxanthinesIsotopesKnock-outLipidsMaintenanceMalignant NeoplasmsMammalian CellMass Spectrum AnalysisMeasurementMediatingMetabolicMethodsMitochondriaMolecularMutationNAD+ kinaseNADPNeurodegenerative DisordersNeurologicNeurologic SymptomsNucleotide BiosynthesisNucleotidesOxidation-ReductionOxidative StressPathway interactionsPatientsPhenotypePhosphatidylinositolsPhosphorylationPhosphotransferasesProductionProliferatingProlineProtein BiosynthesisReactive Oxygen SpeciesRoleScienceSourceSupplementationSupporting CellSymptomsTestingTherapeuticTherapeutic InterventionWithdrawalcell growthcofactorcombatdevelopmental diseasedietary restrictionenzyme biosynthesisexperimental studygene synthesisin vivomacromoleculemutantnervous system disordernovel therapeutic interventionnucleotide metabolismtumortumor growth
项目摘要
SUMMARY: To grow and proliferate, cells need to fulfill three key metabolic demands: increased biosynthesis,
sufficient energy supply, and maintenance of redox homeostasis. The latter demand is particularly important for
sustained growth, because increased rate of cellular metabolic activity during cell proliferation results in elevated
levels of reactive oxygen species (ROS), which can have detrimental effects on cell growth. Nicotinamide
adenine dinucleotide phosphate (NADPH) is a principal supplier of reducing power for biosynthesis of
macromolecules and protection against oxidative stress. The total cellular pool of NADPH is regulated by the
activity of NAD kinases (NADK), enzymes that catalyze the phosphorylation of NAD+ to NADP+, the rate-limiting
substrate for NADPH production. Mammalian cells express two NAD kinases, cytosolic NADK, and mitochondrial
NADK2, which generate compartment-specific reducing power. Recently, we discovered that the activity of
NADK is stimulated by the phosphoinositide 3-kinase (PI3K) - Akt pathway to boost the NADP(H) production for
cell growth, but the importance of NADK2 and the overall role of mitochondrial NADPH in cell growth has yet to
be established. Mutations in NADK2 have been observed in patients with various neurological and
developmental disorders. Therefore, defining the key functions of NADK2 and mitochondrial NADP(H) is critical
and relevant to human health. This proposal builds on our finding that decreasing mitochondrial NADP(H) levels
through depletion of NADK2 renders cells uniquely proline auxotroph. Cells with NADK2 deletion fail to
synthesize proline and rely on exogenous proline for their growth. Proline is critical for protein synthesis, and,
unexpectedly, for nucleotide synthesis, in NADK2-deficient cells. We propose three Specific Aims to establish
the functions of NADK2 and mitochondrial NADP(H) that are essential for cell growth and proliferation and
relevant for proliferative diseases and NADK2 deficiency in humans. In Aim 1, we propose to define the molecular
mechanisms by which NADK2 and mitochondrial NADPH support proline biosynthesis and evaluate the effects
of NADK2 patient mutations on proline synthesis. In Aim 2, we will determine the mechanisms of how NADK2
deficiency and reduced proline abundance affect flux through the de novo and salvage nucleotide synthesis
pathways. In Aim 3, we will assess the requirement of NADK2 and mitochondrial NADPH for tumor growth and
evaluate the therapeutic potential of targeting NADK2 in combination with dietary restriction of proline. This
proposal will establish the primary functions of mitochondrial NADP(H) and NADK2 that are essential for cell
growth and proliferation, thereby informing us on new therapeutic strategies to combat proliferative diseases and
NADK2 deficiency in humans.
摘要:为了生长和增殖,细胞需要满足三个关键的代谢需求:增加生物合成;
项目成果
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Gerta N/A Hoxhaj其他文献
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{{ truncateString('Gerta N/A Hoxhaj', 18)}}的其他基金
Revealing the essential functions of mitochondrial NADPH and NADK2 for cell growth and proliferation
揭示线粒体 NADPH 和 NADK2 对细胞生长和增殖的基本功能
- 批准号:
10487573 - 财政年份:2021
- 资助金额:
$ 32.8万 - 项目类别:
Revealing the essential functions of mitochondrial NADPH and NADK2 for cell growt
揭示线粒体 NADPH 和 NADK2 对细胞生长的基本功能
- 批准号:
10797481 - 财政年份:2021
- 资助金额:
$ 32.8万 - 项目类别:
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