Nicotinamide nucleotide transhydrogenase and bioenergetic metabolism in complex I defective cardiac mitochondria
烟酰胺核苷酸转氢酶和复合物 I 缺陷心脏线粒体中的生物能代谢
基本信息
- 批准号:10360118
- 负责人:
- 金额:$ 43.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:ATP Synthesis PathwayAdrenal gland hypofunctionAffectAgingAnimalsAntioxidantsArrhythmiaBackBioenergeticsBypassCardiacCardiac MyocytesCardiomyopathiesCell RespirationCessation of lifeChildChronicClustered Regularly Interspaced Short Palindromic RepeatsComplexConsumptionCoronary ArteriosclerosisDataDefectDiabetes MellitusDiseaseDisease ProgressionElectron TransportElectron Transport Complex IIIEnzymesFADH2Fatty AcidsGenerationsGoalsHeartHeart DiseasesHeart failureHumanIndividualInheritedInner mitochondrial membraneKnock-outLeadLinkLungMaintenanceMembraneMetabolismMitochondriaMitochondrial DiseasesModelingMusMutationMyocardial dysfunctionNAD(P)+ transhydrogenaseNADPOutcomeOxidation-ReductionOxidative PhosphorylationOxidative StressOxidesPathogenicityPathway interactionsPeroxidesPharmacologyProcessProductionPrognosisProton-Motive ForceProtonsReportingResearchRetinal PhotoreceptorsRoleRotenoneRouteStructurefatty acid oxidationfeedingheart functionheart preservationhuman subjectmouse modelnegative affectnew therapeutic targetoxidationpreventstress reductiontherapeutic targettranslational impact
项目摘要
More than 1 in 5000 children are born with inherited mitochondrial diseases from which 30-40% are complex I
(CI) defects that lead to cardiomyopathy, heart failure and death. A large proportion of chronic conditions
(diabetes, coronary artery disease, heart failure, aging) develop mitochondrial CI defects that are key factors
promoting disease progression and cardiac complications. Pathogenic mechanisms that link CI defect with
heart disease include energy deficit, oxidative stress, and an increased [NADH]. Either inherited or acquired,
mitochondrial CI defects have no cure. We propose a novel therapeutic target that preserves cardiac oxidative
metabolism and function in mitochondrial cardiomyopathies. The objective of this project is to determine if the
mitochondrial enzyme, nicotinamide nucleotide transhydrogenase (NNT), is necessary to sustain cardiac fatty
acid (FA) β-oxidation for ATP production under conditions of reductive stress (increased NADH) caused by a
mitochondrial CI defect. We hypothesize that NADH accumulation induced by a CI defect decreases cardiac
oxidative metabolism thus decreasing FA oxidation and ATP generation, and inducing oxidative stress. An
intact NNT provides an alternate route to consume the excessive NADH and form FADH2 to maintain FA
oxidation and prevent oxidative stress and ATP depletion while preserving cardiac function. First specific aim is
to determine if NNT is necessary to protect the heart function and structure in mitochondrial CI defect. The
second specific aim is to delineate the role of NNT in sustaining complete FA β-oxidation and ATP production
in CI defective mitochondria. The third specific aim is to decipher the contribution of NNT to normalize redox
status and decrease oxidative stress in CI defective mitochondria. Our specific objective aligns with the goal of
our research to cure mitochondrial cardiomyopathies. We will compare hearts, cardiomyocytes and
mitochondria from mice with normal and absent (systemic and cardiac specific) CRISPR NNT knockout on the
C57BL6N background. Rotenone-induced and human-like NDUFS4-deficient cardiac specific CI defects will be
used. Expected outcomes will determine if NNT is a potential therapeutic target to preserve cardiac oxidative
metabolism and function in mitochondrial cardiomyopathy.
每5000名儿童中就有1名以上患有遗传性线粒体疾病,其中30-40%为复合体I
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Georgeta Mariana Rosca其他文献
Georgeta Mariana Rosca的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}














{{item.name}}会员




