Understanding the Mechanisms of Respiratory Supercomplexes and mitochondrial Complex I

了解呼吸超级复合物和线粒体复合物 I 的机制

基本信息

  • 批准号:
    10027204
  • 负责人:
  • 金额:
    $ 37.32万
  • 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:
    2020-08-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT The mitochondrial oxidative phosphorylation electron transport chain (ETC) is composed of five large membrane protein complexes (CI, CII, CIII2, CIV and CV) and is responsible for the production of the majority of cellular ATP. Consequently, the ETC is essential to bioenergetic metabolism. ETC defects are one of the most commonly diagnosed congenital metabolic defects, with CI deficiencies representing roughly a third of these diagnoses. Although ~50% of patients with CI deficiencies die within the first 2 years of life and only ~25% reach 10 years of age, CI remains the least well mechanistically understood of all the ETC complexes. Furthermore, despite the large medical need, there are currently no effective treatments for CI or other ETC deficiencies. This discrepancy stems in part from an incomplete understanding of the molecular mechanisms of the individual complexes and their higher-order assemblies into supercomplexes (SCs). In mammalian heart mitochondria the majority of CI is found in association with CIII2 and CIV (SC I+III2+IV, the respirasome) or in association with CIII2 (SC I+III2). Recent biochemical and structural work has produced the first atomic- resolution structures of mammalian mitochondrial CI and defined the arrangement of the individual complexes within the respirasome and SC I+III2. However, significant questions remain regarding the function, mechanism and regulation of the ETC complexes and SCs. To address these gaps in our understanding and to develop the basic science that will underpin potential treatment strategies of ETC defects, we will establish two major research directions in my lab. Using detailed biochemical and enzymatic analyses together with single particle cryo-electron microscopy structural characterizations, we will elucidate the mechanisms, functions and regulation of 1) isolated CI and 2) respiratory SCs. To achieve this, we propose to perform systematic functional and structural comparisons of respiratory CI and SCs purified from mammalian mitochondria (from both HeLa cell culture and porcine heart tissue), the a-proteobacteria Paracoccus denitrificans and the fungal model system Neurospora crassa. P. denitrificans is one of the closest living organisms to the ancestral a- proteobacteria that originated mitochondria after the endosymbiotic event. N. crassa is an established, powerful genetic and biochemical system for bioenergetics, for which nonetheless no high-resolution ETC structures are available. Comparing the CI and SCs from these divergent and genetically tractable organisms to their mammalian counterparts will allow us to test several key mechanistic hypotheses in the field and to identify the conserved features of CI and SC mechanism and regulation. This will provide deep insights into the energy-converting mechanism of CI and the physiological roles of SC formation, which will define the scientific foundation needed for the development of therapeutic strategies against CI and further ETC deficiencies.
项目总结/文摘

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 }}

James Anthony Letts其他文献

James Anthony Letts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 }}

{{ truncateString('James Anthony Letts', 18)}}的其他基金

Understanding the Mechanisms of Respiratory Supercomplexes and mitochondrial Complex I
了解呼吸超级复合物和线粒体复合物 I 的机制
  • 批准号:
    10219310
  • 财政年份:
    2020
  • 资助金额:
    $ 37.32万
  • 项目类别:
Understanding the Mechanisms of Respiratory Supercomplexes and mitochondrial Complex I
了解呼吸超级复合物和线粒体复合物 I 的机制
  • 批准号:
    10405545
  • 财政年份:
    2020
  • 资助金额:
    $ 37.32万
  • 项目类别:
Understanding the Mechanisms of Respiratory Supercomplexes and mitochondrial Complex I
了解呼吸超级复合物和线粒体复合物 I 的机制
  • 批准号:
    10620828
  • 财政年份:
    2020
  • 资助金额:
    $ 37.32万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.32万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了