Mitochondrial metabolism and the Lon-PDH axis
线粒体代谢和 Lon-PDH 轴
基本信息
- 批准号:10379257
- 负责人:
- 金额:$ 32.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acetyl Coenzyme AAcetylationAnimal ModelArchitectureAstrocytesAtrophicBrainCarbohydratesCatabolismCellsCellular StressCerebrumCitric Acid CycleComplexDataDefectDietary InterventionDiseaseEnergy MetabolismEnergy-Generating ResourcesEnzymesErythrocytesFailureFatty AcidsFibroblastsFunctional disorderGatekeepingGenerationsGenesGlucoseGlutamineGlycolysisGlycolysis InhibitionGoalsHeart DiseasesHumanImpairmentInvestigationKetone BodiesKnowledgeLeucineLinkMalignant NeoplasmsMeasuresMediatingMedium chain fatty acidMetabolicMetabolismMissense MutationMitochondriaModificationMolecularMolecular MachinesMutationNerve DegenerationNeurodegenerative DisordersNeurologicNeurologic DysfunctionsNeuronsOutcomeOxidative PhosphorylationOxidesPDH kinaseParentsPathogenicityPathway interactionsPatientsPharmacologyPhosphorylationPositioning AttributePost-Translational Protein ProcessingProductionProlineProteinsProteolysisProteomicsPyruvatePyruvate Dehydrogenase (Lipoamide)-PhosphatasePyruvate Dehydrogenase ComplexPyruvate Dehydrogenase E1ReactionRegulationSiblingsSkinStreamTestingTranscriptVariantWorkamino acid metabolismbrain celldihydrolipoamide dehydrogenasedihydrolipoyllysine-residue acetyltransferaseendopeptidase Laexperimental studyfatty acid oxidationhigh throughput screeninginduced pluripotent stem cellintermolecular interactionmetabolomicsmitochondrial metabolismmutantnoveloxidationproteostasispyruvate dehydrogenaseresponsestem cell differentiationtherapeutic proteinuptake
项目摘要
The human Lon protease is a master regulator of mitochondrial proteostasis, which is essential for
regulating mitochondrial energy metabolism and mitigating cell stress. We recently identified a novel
pathogenic variant in the LONP1 gene encoding Lon, in two siblings with profound neurologic
impairment, cerebral and cerebellar atrophy, in which proline at position 761 was replaced by leucine
(Lon-P761L). Primary skin fibroblasts from these siblings, showed that the activity of pyruvate
dehydrogenase (PDH) was substantially reduced. PDH deficiency was caused by the failure of Lon-P761L to degrade the phosphorylated E1a subunit of PDH, which accumulates and inhibits PDH
activity. PDH is the central gatekeeper linking glycolysis to the tricarboxylic acid (TCA) cycle, and is
also a key regulatory node for glucose and fatty acid catabolism. Our long term goal is to elucidate why
homozygous Lon-P761L expression causes severe neurologic dysfunction and neurodegeneration.
Glucose is the brain’s principal source of energy. Neurons generate ATP almost exclusively by glucose
oxidization, thus fully functional PDH activity is crucial. Astrocytes by contrast, have broader metabolic
capacity and supply neurons with lactate, glutamine and ketone bodies, which are used to form acetyl
CoA and TCA cycle intermediates required for glucose oxidation. We hypothesize that wild type Lon
regulates the architecture and activities of the PDH complex, and modulates upstream and downstream
effectors, to calibrate mitochondrial metabolism and energetics. In this project, we will employ patient-and parent-derived fibroblasts, and also fibroblasts that have been reprogrammed to generate induced
pluripotent stem cells (iPSCs). These iPSCs will be differentiated into neurons and astrocytes. Using
the patient- and parent- derived fibroblasts, Aim 1 will test the hypothesis that Lon-mediated degradation
regulates the architecture and activity of the PDH complex. Aim 2 will identify the up- and down-stream
modulators of the Lon-PDH axis, which are altered in cells expressing wild type Lon versus Lon-P761L.
In Aim 3, we will investigate the regulation of PDH by Lon in iPSCs differentiated into neurons and
astrocytes. Our investigation will establish new molecular mechanisms for the Lon-dependent
regulation of PDH. The knowledge gained will also help to identify potential therapeutic protein targets
(e.g. PDK, PDP, Lon), pharmacologic and dietary interventions for increasing PDH activity and/or for
treating PDH deficiency associated with Lon dysfunction. These outcomes have a broader impact for
understanding how PDH activity and mitochondrial metabolism can be calibrated in both rare and more
common disorders such as heart disease, cancer and neurodegeneration.
人类Lon蛋白酶是线粒体蛋白质平衡的主要调节因子,这对人体的健康至关重要
项目成果
期刊论文数量(0)
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CAROLYN K SUZUKI其他文献
CAROLYN K SUZUKI的其他文献
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{{ truncateString('CAROLYN K SUZUKI', 18)}}的其他基金
Mitochondrial metabolism and the Lon-PDH axis
线粒体代谢和 Lon-PDH 轴
- 批准号:
10594025 - 财政年份:2020
- 资助金额:
$ 32.17万 - 项目类别:
Mitochondrial metabolism and the Lon-PDH axis
线粒体代谢和 Lon-PDH 轴
- 批准号:
10620384 - 财政年份:2020
- 资助金额:
$ 32.17万 - 项目类别:
Mitochondrial metabolism and the Lon-PDH axis
线粒体代谢和 Lon-PDH 轴
- 批准号:
10728404 - 财政年份:2020
- 资助金额:
$ 32.17万 - 项目类别:
Regulating mtDNA and mtRNA dynamics by the mitochondrial AAA+ Lon protease
通过线粒体 AAA Lon 蛋白酶调节 mtDNA 和 mtRNA 动力学
- 批准号:
9187845 - 财政年份:2015
- 资助金额:
$ 32.17万 - 项目类别:
Mitochondrial chaperones mortalin and Tid1 in protein degradation
蛋白质降解中的线粒体伴侣 mortalin 和 Tid1
- 批准号:
8707617 - 财政年份:2011
- 资助金额:
$ 32.17万 - 项目类别:
Mitochondrial chaperones mortalin and Tid1 in protein degradation
蛋白质降解中的线粒体伴侣 mortalin 和 Tid1
- 批准号:
8192595 - 财政年份:2011
- 资助金额:
$ 32.17万 - 项目类别:
Mitochondrial chaperones mortalin and Tid1 in protein degradation
蛋白质降解中的线粒体伴侣 mortalin 和 Tid1
- 批准号:
8311645 - 财政年份:2011
- 资助金额:
$ 32.17万 - 项目类别:
High throughput screening assays to identify small molecules that target the ClpX
通过高通量筛选分析来识别靶向 ClpX 的小分子
- 批准号:
7994954 - 财政年份:2010
- 资助金额:
$ 32.17万 - 项目类别:
High throughput screens for modulators of mitochondrial ATP-dependent proteolysis
高通量筛选线粒体 ATP 依赖性蛋白水解调节剂
- 批准号:
7914479 - 财政年份:2009
- 资助金额:
$ 32.17万 - 项目类别:
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