Mechanisms and therapeutic potential of blocking the mitochondrial Mg2+ channel Mrs2 in obesity and NAFLD
阻断线粒体 Mg2 通道 Mrs2 在肥胖和 NAFLD 中的机制和治疗潜力
基本信息
- 批准号:10679847
- 负责人:
- 金额:$ 55.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdipocytesAdipose tissueAdoptedAnimalsBiochemicalBiochemistryBioenergeticsBiologicalBody CompositionBody WeightBrown FatCRISPR/Cas technologyCardiovascular DiseasesCell physiologyCellsChronic Kidney FailureCitratesClinicalDataDetectionDevelopmentDiabetes MellitusDiseaseDisease ProgressionDisease modelDivalent CationsEnergy MetabolismEukaryotaEventFailureFatty LiverFatty acid glycerol estersFunctional disorderGene Expression ProfileGeneticGlucoseGlycolysisHIF1A geneHealthHepaticHepatocyteHomeostasisHyperglycemiaImpairmentIn VitroInterventionIon ChannelKnockout MiceLigandsLinkLipidsLiverLiver MitochondriaMagnesiumMalignant NeoplasmsMeasuresMediatingMetabolicMetabolic DiseasesMetabolic PathwayMetabolismMigraineMitochondriaMitochondrial RNAModelingMolecularMusNon-Insulin-Dependent Diabetes MellitusObesityPathologic ProcessesPathway interactionsPatientsPhenotypePhysiologicalPhysiologyPlasmaPlayPre-EclampsiaPrevalencePublic HealthQuality ControlRNA SplicingRegulationRoleSepsisSignal TransductionStressStructureTestingTherapeuticTriglyceridesWeight Gainbiophysical techniquesblood glucose regulationcandidate identificationcomorbiditydiet-induced obesitydietarydietary controlexperimental studyfatty acid oxidationfeedingfibroblast growth factor 21genetic approachgenetic regulatory proteinglucose metabolismglucose productionin vivoinnovationinsightinterestlipid biosynthesislipid metabolismliver functionliver metabolismmouse modelnervous system disordernon-alcoholic fatty liver diseasenovel therapeutic interventionobesity preventionoxidationpharmacologicpreservationpreventrespiratoryrestorationsmall moleculetranscriptome sequencingtreatment strategyuptakewestern diet
项目摘要
ABSTRACT
Aberrant hepatic glucose and lipid metabolism is a feature of several prevalent metabolic disorders, including
obesity, type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Increased hepatic glucose
production directly contributes to hyperglycemia in patients with T2DM, and hepatic steatosis is the defining
feature of NAFLD. The increased prevalence of T2DM and NAFLD present a significant threat to public health,
and treatment strategies that address the underlying pathological processes are urgently needed. Although Ca2+
signaling in metabolic disease is emerging, the potential reciprocal role of Mg2+ dynamics on mitochondrial
bioenergetics is much less understood and is the focus of the current proposal. In preliminary studies, we
generated a global KO model of the mitochondrial Mg2+ transporter Mrs2 using CRISPR/Cas9 and examined the
impact on hepatic metabolism (Daw et al Cell 2020). Interestingly, loss of Mrs2 impairs mMg2+ uptake and
prevents hepatic steatosis in vivo. This is associated with increased mitochondrial respiratory capacity in
hepatocytes and markedly enhanced browning of white adipose tissue, indicative of increased capacity for
energy expenditure. Using innovative, unbiased RNA-seq, animal physiology studies, molecular, cell biological,
biochemistry and biophysical approaches, we have identified candidate pathways linking Mrs2-mediated mMg2+
uptake to mitochondrial suppression of OXPHOS and fatty acid oxidation under WD. Remarkably, the elevation
of de novo lipogenesis precursor citrate is blunted in Mrs2 KO mice and thus controls diet induced obesity. Based
on these preliminary data, we hypothesize that Mrs2-mediated mMg2+ uptake is a key determinant of
mitochondrial bioenergetic failure in the liver during disease progression, and that mitigating excess mMg2+
uptake using a small molecule blocker of the Mrs2 channel activity will prevent the development of NAFLD
through restoration of signaling and mitochondrial bioenergetics. The overall aim of the current proposal is to
identify molecular signals that are controlled by mMg2+ dynamics, and their impact on bioenergetics and
mitochondrial quality control, and to describe the molecular mechanisms linking Mrs2 to key hepatic metabolic
pathways that are dysregulated in metabolic diseases. Using a combination of integrative in vitro and in vivo
approaches, we will perform mechanistic studies to determine the impact of disrupted intracellular Mg2+ signals
on mitochondrial function, hepatic lipid and glucose metabolism, whole-body energy homeostasis, and the
progression of NAFLD. Given these preliminary findings, in Specific Aim 1 of the proposal we will employ our
unique mouse model to examine the role of Mrs2 and mMg2+ uptake on mitochondrial function in hepatocytes
and will determine the impact of impaired mMg2+ uptake on hepatic and whole-body glucose and lipid metabolism.
In Specific Aim 2, we will investigate the role of citrate in Hif-1α dependent signaling that is altered in Mrs2 KO,
which ultimately restores mitochondrial energetics and quality control. Finally, in Specific Aim 3, we will use both
genetic and pharmacologic interventions to evaluate the significance of MRS2 in NAFLD models.
摘要
肝脏葡萄糖和脂肪代谢异常是几种普遍的代谢紊乱的特征,包括
肥胖、2型糖尿病(T2 DM)和非酒精性脂肪性肝病(NAFLD)。肝脏血糖升高
代谢产物直接导致T2 DM患者的高血糖,而肝脏脂肪变性是其定义
非酒精性脂肪肝的特点。2型糖尿病和非酒精性脂肪肝患病率的增加对公众健康构成了重大威胁,
迫切需要针对潜在病理过程的治疗策略。虽然钙离子
代谢性疾病中的信号正在浮现,镁离子动力学在线粒体上的潜在交互作用
人们对生物能量学的了解要少得多,它是当前提案的重点。在初步研究中,我们
使用CRISPR/Cas9建立了线粒体镁离子转运体MRS2的全局KO模型,并研究了
对肝脏新陈代谢的影响(Daw Et Al Cell 2020)。有趣的是,mrs2的缺失会损害mMg2+的摄取和
在体内防止肝脏脂肪变性。这与线粒体呼吸能力的增加有关。
肝细胞和明显增强的白色脂肪组织的褐变,表明
能源支出。使用创新的、无偏见的RNA-SEQ,动物生理学研究,分子,细胞生物学,
生物化学和生物物理方法,我们已经确定了连接MRS-2介导的mMg2+的候选途径
WD对线粒体摄取OXPHOS和脂肪酸氧化的抑制作用。值得注意的是,海拔
在mrs2KO小鼠中,从头脂肪生成前体柠檬酸盐被钝化,从而控制饮食诱导的肥胖。基座
根据这些初步数据,我们假设mrs2介导的mmg2+摄取是
疾病进展过程中肝脏线粒体生物能衰竭,以及减轻过量mMg2+的作用
使用小分子阻断剂阻断mrs2通道活性可阻止NAFLD的发展
通过恢复信号和线粒体生物能量学。目前提案的总体目标是
确定由mMg2+动力学控制的分子信号及其对生物能量学和
线粒体质量控制,并描述将mrs2与关键肝脏代谢联系起来的分子机制
代谢性疾病中调节失调的通路。使用体外和体内一体化的组合
我们将进行机制研究,以确定细胞内镁离子信号中断的影响
对线粒体功能、肝脏脂肪和葡萄糖代谢、全身能量平衡以及
非酒精性脂肪肝的进展。鉴于这些初步调查结果,在提案的具体目标1中,我们将采用我们的
独特的小鼠模型研究mRs2和mMg2+摄取对肝细胞线粒体功能的影响
并将确定mMg2+摄取受损对肝脏和全身糖脂代谢的影响。
在特定的目标2中,我们将研究柠檬酸在Hif-1α依赖的信号转导中的作用,该信号在mrs2KO中改变,
最终恢复线粒体的能量学和质量控制。最后,在具体的目标3中,我们将使用这两个
遗传和药物干预以评估MRS2在NAFLD模型中的意义。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph A. Baur其他文献
Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome
人类遗传学确定了心血管-肾脏-代谢综合征中线粒体 LACTB 介导的脂质代谢中的趋同信号。
- DOI:
10.1016/j.cmet.2024.10.007 - 发表时间:
2025-01-07 - 期刊:
- 影响因子:30.900
- 作者:
Shen Li;Hongbo Liu;Hailong Hu;Eunji Ha;Praveena Prasad;Brenita C. Jenkins;Ujjalkumar Subhash Das;Sarmistha Mukherjee;Kyosuke Shishikura;Renming Hu;Daniel J. Rader;Liming Pei;Joseph A. Baur;Megan L. Matthews;Garret A. FitzGerald;Melanie R. McReynolds;Katalin Susztak - 通讯作者:
Katalin Susztak
Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease
线粒体 NAD+转运蛋白 SLC25A51 与人类主动脉疾病相关
- DOI:
10.1038/s44161-024-00599-6 - 发表时间:
2025-01-22 - 期刊:
- 影响因子:10.800
- 作者:
Gabriel K. Adzika;Ricardo A. Velázquez Aponte;Joseph A. Baur - 通讯作者:
Joseph A. Baur
Swine Models for NAD + Supplementation in Heart Failure
补充 NAD 治疗心力衰竭的猪模型
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Joseph A. Baur - 通讯作者:
Joseph A. Baur
Resveratrol for primary prevention of atherosclerosis: Clinical trial evidence for improved gene expression in vascular endothelium
- DOI:
10.1016/j.ijcard.2012.09.027 - 发表时间:
2013-06-05 - 期刊:
- 影响因子:
- 作者:
Beamon Agarwal;Matthew J. Campen;Meghan M. Channell;Sarah J. Wherry;Behzad Varamini;James G. Davis;Joseph A. Baur;James M. Smoliga - 通讯作者:
James M. Smoliga
Regulation of and challenges in targeting NAD+ metabolism
靶向 NAD+代谢的调控与挑战
- DOI:
10.1038/s41580-024-00752-w - 发表时间:
2024-07-18 - 期刊:
- 影响因子:90.200
- 作者:
Marie E. Migaud;Mathias Ziegler;Joseph A. Baur - 通讯作者:
Joseph A. Baur
Joseph A. Baur的其他文献
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{{ truncateString('Joseph A. Baur', 18)}}的其他基金
HTS to identify compounds that increase NAD+ levels in neurons and muscle cells
HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物
- 批准号:
10665088 - 财政年份:2022
- 资助金额:
$ 55.8万 - 项目类别:
Understanding the roles of cardiac NAD pools and therapeutic effects of precursor supplements in heart failure
了解心脏 NAD 池的作用以及前体补充剂对心力衰竭的治疗作用
- 批准号:
10539858 - 财政年份:2022
- 资助金额:
$ 55.8万 - 项目类别:
Understanding the roles of cardiac NAD pools and therapeutic effects of precursor supplements in heart failure
了解心脏 NAD 池的作用以及前体补充剂对心力衰竭的治疗作用
- 批准号:
10680576 - 财政年份:2022
- 资助金额:
$ 55.8万 - 项目类别:
HTS to identify compounds that increase NAD+ levels in neurons and muscle cells
HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物
- 批准号:
10618481 - 财政年份:2022
- 资助金额:
$ 55.8万 - 项目类别:
Mechanisms underlying the genetic association between PPP1R3B and Alzheimer's Disease
PPP1R3B 与阿尔茨海默病之间遗传关联的潜在机制
- 批准号:
10288770 - 财政年份:2018
- 资助金额:
$ 55.8万 - 项目类别:
Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis
PPP1R3B与肝脂肪变性遗传关联的分子机制
- 批准号:
10224175 - 财政年份:2018
- 资助金额:
$ 55.8万 - 项目类别:
Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态
- 批准号:
10288703 - 财政年份:2013
- 资助金额:
$ 55.8万 - 项目类别:
Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态
- 批准号:
8596305 - 财政年份:2013
- 资助金额:
$ 55.8万 - 项目类别:
Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态
- 批准号:
8731882 - 财政年份:2013
- 资助金额:
$ 55.8万 - 项目类别:
Molecular Mechanisms of Rapamycin's effects on Health and longevity.
雷帕霉素对健康和长寿影响的分子机制。
- 批准号:
8852520 - 财政年份:2013
- 资助金额:
$ 55.8万 - 项目类别:
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