Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease
血红素相关线粒体抗氧化剂 ABCB10 在酒精性肝病中的作用
基本信息
- 批准号:10201420
- 负责人:
- 金额:$ 35.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseATP-Binding Cassette TransportersAlcoholic HepatitisAlcoholic Liver DiseasesAntioxidantsBilirubinBiliverdin reductaseBiliverdineCessation of lifeCirrhosisClinical TrialsCysteineCytosolDataDefectDependenceDisease ProgressionEffectivenessEngineeringEquilibriumEthanolGlutathioneHemeHepaticHepatitisHepatocyteHumanHydrogen PeroxideImpairmentInner mitochondrial membraneKnockout MiceLiverLiver MitochondriaMeasuresMediatingMembraneMitochondriaMitochondrial MatrixMolecularMusNatural regenerationOrganellesOxidation-ReductionOxidative StressPatientsPost-Translational RegulationProcessProductionProteinsPublic HealthReactive Oxygen SpeciesRoleSeverity of illnessSulfinic AcidsSulfonic AcidsSystemTestingTimeVirulence Factorsfluorescence imaginggain of functionheme oxygenase-1hydrophilicityin vivolive cell imagingliver biopsyliver functionmitochondrial dysfunctionmouse modelmutantoverexpressionoxidationoxidative damagepreventstemsuccess
项目摘要
Project Summary
Alcoholic liver disease (ALD) causes 48% of cirrhotic deaths derived from hepatitis. Increased reactive oxygen
species (ROS) production is a major pathogenic factor leading the progression of ALD from steatosis to alcoholic
hepatitis (AH). However, clinical trials testing compounds that unselectively scavenge ROS or enhance
acquainted antioxidants were unsuccessful. This lack of success supports that ALD disrupts endogenous
antioxidant systems inside mitochondria, an organelle formed by two membranes that limit the entry and action
of the compounds tested. Our proposal stems from our identification of a mitochondrial antioxidant and redox
system impaired in ALD and previously unknown in liver. This system is constituted by the mitochondrial inner
membrane ATP binding cassette transporter ABCB10, which exports a previously unknown cargo through its
ATP hydrolysis activity (ATPase). Our preliminary data supports that ABCB10 decreases ALD severity by
decreasing ROS-mediated damage, as liver-specific deletion of ABCB10 exacerbates hepatic oxidative damage
and ALD severity in mice. We hypothesize that ABCB10 transport activity protects from ALD by limiting
EtOH-induced oxidative damage. Remarkably, our new data shows that ABCB10 content is decreased in late-
stage ALD, including mice and humans with AH. Mechanistically, we show for the first time that ABCB10 exports
Biliverdin (BV) from the mitochondrial matrix to the cytosol, where biliverdin reductase (BLVR) is located.
Exported BV is used by cytosolic BLVR to regenerate intracellular Bilirubin (BR) destined for ROS scavenging.
We hypothesize that ABCB10-mediated BV export is decreased in ALD, shrinking the intrahepatocyte
BR pool that protects from ROS-mediated damage. Accordingly, our data show that: i) EtOH and ABCB10
deletion reduce intrahepatocyte BR levels and ii) ABCB10 deletion causes mitochondrial BV accumulation and
increases intracellular ROS levels. Thus, we will: 1) Determine the role of ABCB10 in ALD in vivo and 2)
Determine the mechanism by which ABCB10 modulates oxidative stress in ALD.
项目总结
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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Orian S Shirihai其他文献
Cardiac-Specific Fatty Acid Transport Protein 1 (FATP1) Overexpression Causes Decreased Mitochondrial Respiration, Increased Oxidative Stress and Activation of AMPK
- DOI:
10.1016/j.freeradbiomed.2012.10.434 - 发表时间:
2012-11-01 - 期刊:
- 影响因子:
- 作者:
Aly Elezaby;Edward J Miller;Fuzhong Qin;Marc Liesa;Orian S Shirihai;Wilson S Colucci - 通讯作者:
Wilson S Colucci
Orian S Shirihai的其他文献
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{{ truncateString('Orian S Shirihai', 18)}}的其他基金
MITOCHONDRIAL RESPIROMETRY IN FROZEN BIOLOGICAL SAMPLES
冷冻生物样品中的线粒体呼吸测定
- 批准号:
10251412 - 财政年份:2021
- 资助金额:
$ 35.1万 - 项目类别:
MITOCHONDRIAL RESPIROMETRY IN FROZEN BIOLOGICAL SAMPLES
冷冻生物样品中的线粒体呼吸测定
- 批准号:
10011475 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease
血红素相关线粒体抗氧化剂 ABCB10 在酒精性肝病中的作用
- 批准号:
10443585 - 财政年份:2019
- 资助金额:
$ 35.1万 - 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
- 批准号:
7645363 - 财政年份:2007
- 资助金额:
$ 35.1万 - 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
- 批准号:
8012816 - 财政年份:2007
- 资助金额:
$ 35.1万 - 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
- 批准号:
7346916 - 财政年份:2007
- 资助金额:
$ 35.1万 - 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
- 批准号:
7535553 - 财政年份:2007
- 资助金额:
$ 35.1万 - 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
- 批准号:
7212876 - 财政年份:2007
- 资助金额:
$ 35.1万 - 项目类别:
FUNCTIONAL HETEROGENEITY OF MITOCHONDRIA IN AN INDIVIDUAL PANCREATIC BETA CELL
单个胰腺β细胞中线粒体的功能异质性
- 批准号:
7357321 - 财政年份:2005
- 资助金额:
$ 35.1万 - 项目类别:














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