Regulation of mitochondrial dynamics by ERAD

ERAD 调节线粒体动力学

• 批准号: 10595515
• 负责人: Ling Qi
• 金额: $ 27.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595515
• 关键词: Adipocytes; Biology; Cell physiology; Cells; Complex; Cytosol; Data; Dedications; Disease; Endoplasmic Reticulum; Equilibrium; Exhibits; Face; Feedback; Freedom; Functional disorder; Funding; Goals; Grant; Health; Human; Laboratories; Lead; Mammals; Mitochondria; Molecular; Morphology; National Institute of General Medical Sciences; Organelles; Pathogenesis; Pathway interactions; Physiological; Physiology; Positioning Attribute; Process; Proteins; Quality Control; Regulation; Reporting; Resources; Role; Signal Transduction; System; Testing; Time; cell type; human disease; innovation; insight; interest; misfolded protein; novel; protein complex; protein degradation; protein folding; response; restraint; sensor

Regulation of Mitochondrial Dynamics by ERAD ABSTRACT Cells face a complex challenge of balancing protein folding and degradation in the endoplasmic reticulum (ER), a multifunctional organelle that is central to human health. Further, dysregulation of this balance accounts for the pathogenesis of many human diseases. ER-associated degradation (ERAD) is a principal quality-control mechanism used by the cells to target misfolded proteins in the ER for proteasomal degradation in the cytosol. However, the physiological function of distinct mammalian ERAD components remain largely unclear. In the last several years, we have explored the physiological importance of cell type-specific ERAD in normal physiology and disease, and have identified molecular substrates and pathways underpinning ERAD- associated pathophysiology. While ERAD expression is known to be controlled by IRE1a signaling of the UPR, we recently discovered a negative feedback loop in which the Sel1L-Hrd1 protein complex of mammalian ERAD restrains IRE1a signaling and activation under the steady state by targeting IRE1a for proteasomal degradation. This study demonstrates an intimate crosstalk between the two most conserved ER quality- control systems. Surprisingly, our recent data in brown adipocytes reveals that Sel1L-Hrd1 ERAD may regulate mitochondrial dynamics, in part via IRE1a. Sel1L-deficient brown adipocytes exhibit a profound morphological alteration of mitochondria in response to cold exposure, which can be partially rescued upon the deletion of IRE1a. One of the major goals for the next five years is to delineate the molecular mechanism underlying the regulation of mitochondrial dynamics by ERAD by testing the overarching hypothesis that Sel1L-Hrd1 ERAD regulates mitochondrial dynamics and function via IRE1a. We will explore whether and how the “Sel1L- Hrd1 ERAD-IRE1a” axis of ER quality control machineries exerts control over mitochondrial fission-fusion balance. This study may not only reveal the significance of an “ERAD-UPR” crosstalk at the core of normal cellular function and physiology, but may also provide exciting insights into the organelle crosstalk, a largely mysterious process. With funding support from NIGMS, we have made great progress towards the understanding of the ERAD- UPR biology in mammals in the past several years. Hence, we are uniquely positioned to lead this project with innovation, passion and dedication to scientific discovery. The R35 grant mechanism will give us the intellectual freedom, time and resources to direct our energy for exploration into discovery and will open up new directions to provide unprecedented insights into the role of ER quality-control machineries in mitochondrial biology.

ERAD对线粒体动力学的调控 摘要 细胞面临着平衡内质网（ER）中蛋白质折叠和降解的复杂挑战， 一种对人类健康至关重要的多功能细胞器。此外，这种平衡失调导致了 许多人类疾病的发病机理。ER相关降解（ERAD）是主要的质量控制 细胞用于靶向ER中错误折叠的蛋白质以在胞质溶胶中进行蛋白酶体降解的机制。 然而，不同的哺乳动物ERAD组件的生理功能仍然很大程度上不清楚。在 在过去的几年里，我们已经探索了正常人中细胞类型特异性ERAD的生理重要性。 生理学和疾病，并已确定的分子底物和途径的基础ERAD- 相关病理生理学虽然已知ERAD表达受UPR的IRE 1a信号传导控制， 我们最近发现了一个负反馈回路，在这个回路中，哺乳动物的Sel 1 L-Hrd 1蛋白复合物 ERAD通过靶向IRE 1a蛋白酶体抑制IRE 1a信号传导和稳态下的激活 降解这项研究表明，两个最保守的ER质量之间的亲密串扰- 控制系统令人惊讶的是，我们最近在棕色脂肪细胞中的数据显示，Sel 1 L-Hrd 1 ERAD可能调节 线粒体动力学，部分通过IRE 1a。Sel 1 L缺陷棕色脂肪细胞表现出深刻的形态学特征 线粒体对冷暴露的反应改变，这可以在删除 IRE1a。未来五年的主要目标之一是阐明 通过检验Sel 1 L-Hrd 1 ERAD的总体假设， 通过IRE 1a调节线粒体动力学和功能。我们将探讨是否以及如何“Sel 1 L- ER质量控制机制的“Hrd 1 ERAD-IRE 1a”轴对线粒体分裂-融合施加控制 平衡这项研究可能不仅揭示了在正常的核心“ERAD-UPR”串扰的意义， 细胞功能和生理学，但也可能提供令人兴奋的见解细胞器串扰，在很大程度上 神秘的过程 在NIGMS的资助下，我们在理解ERAD方面取得了很大进展- 在过去的几年里，哺乳动物的普遍定期审议生物学。因此，我们处于独特的地位，领导这个项目， 创新、激情和对科学发现的奉献精神。R35赠款机制将为我们提供 智力自由、时间和资源，将我们的探索精力引向发现， 新的方向，以提供前所未有的洞察ER质量控制机械的作用， 线粒体生物学