Regulation of mitochondrial dynamics by ERAD

ERAD 调节线粒体动力学

• 批准号: 9934815
• 负责人: Ling Qi
• 金额: $ 6.07万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9934815
• 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; 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.

通过ERAD调节线粒体动力学 抽象的 细胞面临平衡蛋白质折叠和降解的复杂挑战，内质网（ER）， 一种对人类健康至关重要的多功能细胞器。此外，此余额的失调占 许多人类疾病的发病机理。与ER相关的降解（ERAD）是主要质量控制 细胞用来靶向ER中错误折叠的蛋白质的机制，以使细胞质中的蛋白酶体降解。 然而，不同哺乳动物的ERAD成分的物理功能在很大程度上不清楚。在 最近几年，我们探讨了正常细胞类型特异性iRAD的身体重要性 生理学和疾病，并确定了分子底物和途径 相关的病理生理学。虽然已知ERAD表达受到UPR的IRE1A信号的控制，但 我们最近发现了一个负反馈循环，其中哺乳动物的SEL1L-HRD1蛋白复合物 ERAD通过靶向蛋白酶体来限制稳态下的IRE1A信号传导和激活 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表明，SEL1L-HRD1 ERAD可能会调节 线粒体动力学，部分通过IRE1A。 SEL1L缺乏的棕色脂肪细胞暴露了一个深刻的形态学 线粒体响应寒冷暴露的改变，这可以部分响应于删除 IRE1A。接下来五年的主要目标之一是描述分子机制 通过测试SEL1L-HRD1 ERAD的总体假设，通过ERAD调节线粒体动力学 通过IRE1A调节线粒体动力学和功能。我们将探讨“ sel1l-”是否以及如何 HRD1 ERAD-ire1a” ER质量控制机的轴对线粒体裂变施加控制 平衡。这项研究不仅可能揭示了正常核心的“ Erad-upr”串扰的重要性 细胞功能和生理学，但也可能为细胞器串扰提供令人兴奋的见解，很大程度上是 神秘的过程。 在Nigms的资金支持下，我们在理解Erad的理解方面取得了长足的进步 - 在过去的几年中，哺乳动物的UPR生物学。因此，我们在领导这个项目的独特位置 创新，热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，以指导我们的精力探索发现，并将开放 新的方向以提供前所未有的见解，以了解ER质量控制机在 线粒体生物学。