Molecular control of CPT-I and CD36 in the regulation of mitochondrial fatty acid transport
CPT-I和CD36在线粒体脂肪酸转运调节中的分子控制
基本信息
- 批准号:RGPIN-2019-05113
- 负责人:
- 金额:$ 3.42万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2020
- 资助国家:加拿大
- 起止时间:2020-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Mitochondria influence several processes, including energy provision, apoptosis, calcium handling and redox balance, and as result are now recognized as a key organelle that influences homeostasis in almost every cell. A fundamental event influencing mitochondrial biology is the movement of long-chain fatty acids across the outer/inner mitochondrial membranes. While our understanding of the basic mechanisms regulating this process remains incomplete, carnitine palmitoyltransferase-I (CPT-I) and CD36 play key roles.
While CPT-I is required mitochondrial membrane lipid transport, we aim to establish if cellular stresses can alter the sensitivity of CPT-I to various substrates, how CPT-I is regulated and what the biological consequence is to changes in catalytic flux through this enzyme. We plan to address these knowledge gaps by determining potential post-translational modifications of CPT-I during increased cellular stress (e.g. acute exercise). We anticipate that various serine residues will be phosphorylated during exercise (i.e. S330, S572, S401, S402 and S610) in association with changes in the biochemical properties of CPT-I, and therefore plan to transiently express mutated CPT-I constructs (i.e. alanine substitutions for serine to prevent phosphorylation) in a muscle specific knock out animal to study the impact on various mitochondrial and cellular parameters. This approach will enable us to determine cause-and-effect relationships between alterations in CPT-I phosphorylation, enzymatic flux, mitochondrial bioenergetics and cellular homeostasis.
We have also identified that cellular stress can induce the movement of a protein (CD36) from an intracellular region to mitochondrial membranes. CD36 appears to be located upstream of CPT-I, where an accumulation influences the delivery of lipids to CPT-I to indirectly influence membrane transport, however, the molecular basis for this subcellular trafficking remains unknown. We plan to determine if the C-terminal YCACR motif of CD36 interacts with various signaling events to influence this cellular process. To achieve this, we will transiently transfect wild type and C-terminal mutants (C-terminal amino acids deleted) into the skeletal muscle of CD36 knock out mice. Thereafter we will provide metabolic challenges (e.g. muscle contraction) and determine the ability of CD36 to accumulate on mitochondrial membranes and the functional consequence. To determine the necessity of specific signalling events in mediating mitochondrial CD36 trafficking, similar experiments in genetically modified mice or with pharmacological inhibitors will be employed.
Combined, the proposed studies will provide fundamental knowledge on the mechanisms regulating mitochondrial lipid transport, a process that has broad implications to understanding cellular homeostasis.
线粒体影响几个过程,包括能量供应,细胞凋亡,钙处理和氧化还原平衡,因此现在被认为是影响几乎每个细胞内稳态的关键细胞器。 影响线粒体生物学的一个基本事件是长链脂肪酸穿过线粒体外/内膜的运动。虽然我们对调节这一过程的基本机制的理解仍然不完整,但肉毒碱棕榈酰转移酶-I(CPT-I)和CD 36起着关键作用。
虽然CPT-I需要线粒体膜脂质转运,我们的目标是建立细胞应激是否可以改变CPT-I对各种底物的敏感性,CPT-I是如何调节的,以及通过这种酶的催化通量变化的生物学后果是什么。 我们计划通过确定细胞应激增加(例如急性运动)期间CPT-1的潜在翻译后修饰来解决这些知识缺口。我们预期在运动过程中各种丝氨酸残基将被磷酸化(即S330、S572、S401、S402和S610)与CPT-1的生化性质的变化相关,因此计划瞬时表达突变的CPT-1构建体(即丙氨酸取代丝氨酸以防止磷酸化)在肌肉特异性敲除动物中研究对各种线粒体和细胞参数的影响。这种方法将使我们能够确定CPT-I磷酸化,酶通量,线粒体生物能量学和细胞内稳态的改变之间的因果关系。
我们还发现,细胞应激可以诱导蛋白质(CD 36)从细胞内区域移动到线粒体膜。CD 36似乎位于CPT-I的上游,其中的积累影响脂质向CPT-I的递送,从而间接影响膜转运,然而,这种亚细胞运输的分子基础仍然未知。我们计划确定CD 36的C-末端YCACR基序是否与各种信号事件相互作用以影响该细胞过程。为了实现这一点,我们将野生型和C-末端突变体(C-末端氨基酸缺失)瞬时转染到CD 36敲除小鼠的骨骼肌中。此后,我们将提供代谢挑战(例如肌肉收缩),并确定CD 36在线粒体膜上积累的能力和功能后果。为了确定特定信号传导事件在介导线粒体CD 36运输中的必要性,将在遗传修饰小鼠中或使用药理学抑制剂进行类似实验。
结合起来,拟议的研究将提供关于调节线粒体脂质转运机制的基础知识,这一过程对理解细胞内稳态具有广泛的意义。
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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Holloway, Graham其他文献
Holloway, Graham的其他文献
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{{ truncateString('Holloway, Graham', 18)}}的其他基金
Molecular control of CPT-I and CD36 in the regulation of mitochondrial fatty acid transport
CPT-I和CD36在线粒体脂肪酸转运调节中的分子控制
- 批准号:
RGPIN-2019-05113 - 财政年份:2022
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Molecular control of CPT-I and CD36 in the regulation of mitochondrial fatty acid transport
CPT-I和CD36在线粒体脂肪酸转运调节中的分子控制
- 批准号:
RGPIN-2019-05113 - 财政年份:2021
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Modern exercise suite for basic research in small rodents
用于小型啮齿动物基础研究的现代运动套件
- 批准号:
RTI-2021-00201 - 财政年份:2020
- 资助金额:
$ 3.42万 - 项目类别:
Research Tools and Instruments
Molecular control of CPT-I and CD36 in the regulation of mitochondrial fatty acid transport
CPT-I和CD36在线粒体脂肪酸转运调节中的分子控制
- 批准号:
RGPIN-2019-05113 - 财政年份:2019
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Understanding basic regulation of mitochondrial bioenergetics and adaptations to exercise
了解线粒体生物能量学的基本调节和运动适应
- 批准号:
RGPIN-2014-03656 - 财政年份:2018
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Comprehensive assessment of mitochondrial bioenergetics; enabling simultaneous measurements in controlled oxygen environments
线粒体生物能量学综合评估;
- 批准号:
RTI-2018-00283 - 财政年份:2017
- 资助金额:
$ 3.42万 - 项目类别:
Research Tools and Instruments
Understanding basic regulation of mitochondrial bioenergetics and adaptations to exercise
了解线粒体生物能量学的基本调节和运动适应
- 批准号:
RGPIN-2014-03656 - 财政年份:2017
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Understanding basic regulation of mitochondrial bioenergetics and adaptations to exercise
了解线粒体生物能量学的基本调节和运动适应
- 批准号:
RGPIN-2014-03656 - 财政年份:2016
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Understanding basic regulation of mitochondrial bioenergetics and adaptations to exercise
了解线粒体生物能量学的基本调节和运动适应
- 批准号:
RGPIN-2014-03656 - 财政年份:2015
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Understanding basic regulation of mitochondrial bioenergetics and adaptations to exercise
了解线粒体生物能量学的基本调节和运动适应
- 批准号:
RGPIN-2014-03656 - 财政年份:2014
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
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