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Lon蛋白酶是线粒体蛋白质稳态的主要调节剂,其对于维持线粒体的蛋白质稳态是必需的。
调节线粒体能量代谢,缓解细胞应激。我们最近发现了一本小说
编码Lon的LONP 1基因的致病性变异,在两个患有严重神经系统疾病的兄弟姐妹中
损伤,大脑和小脑萎缩,其中761位的脯氨酸被亮氨酸取代
(Lon-P761L)。来自这些兄弟姐妹的原代皮肤成纤维细胞,显示丙酮酸的活性
脱氢酶(PDH)的活性显著降低。PDH缺陷是由于Lon-P761 L不能降解磷酸化的PDH的E1 a亚基,从而积累和抑制PDH
活动PDH是连接糖酵解与三羧酸(TCA)循环的中心看门人,
也是葡萄糖和脂肪酸催化剂的关键调节节点。我们的长期目标是阐明为什么
纯合Lon-P761 L表达导致严重的神经功能障碍和神经变性。
葡萄糖是大脑的主要能量来源。神经元几乎完全通过葡萄糖产生ATP
氧化,因此功能齐全的PDH活性至关重要。相比之下,星形胶质细胞具有更广泛的代谢
容量和供应神经元乳酸,谷氨酰胺和酮体,用于形成乙酰
葡萄糖氧化所需的CoA和TCA循环中间体。我们假设野生型Lon
调节PDH复合物的结构和活性,并调节上游和下游
效应器,以校准线粒体代谢和能量学。在这个项目中,我们将采用患者和父母来源的成纤维细胞,以及已经重新编程以产生诱导的成纤维细胞。
多能干细胞(iPSC)。这些iPSC将分化为神经元和星形胶质细胞。使用
患者和亲本来源的成纤维细胞,目的1将检验Lon介导的降解
调节PDH复合物的结构和活性。目标2将确定上游和下游
Lon-PDH轴的调节剂,其在表达野生型Lon的细胞中相对于Lon-P761 L发生改变。
在目标3中,我们将研究Lon在分化为神经元的iPSC中对PDH的调节,
星形胶质细胞。我们的研究将建立新的分子机制,
PDH的调节。所获得的知识也将有助于确定潜在的治疗蛋白质靶点
(e.g. PDK、PDP、Lon)、用于增加PDH活性和/或用于
治疗与Lon功能障碍相关的PDH缺乏症。这些成果对以下方面产生了更广泛的影响:
了解PDH活性和线粒体代谢如何在罕见和更多的情况下进行校准,
常见的疾病,如心脏病、癌症和神经退化。
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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