Acylations: a novel pathway in the response to mitochondrial energy dysfunction

酰化：应对线粒体能量功能障碍的新途径

基本信息

批准号：
10342557
负责人：
Jennifer Q. Kwong
金额：
$ 31.3万
依托单位：
EMORY UNIVERSITY
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：
2022-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10342557
关键词：
ATP Synthesis Pathway Acetylation Acylation Acyltransferase Adult Affect Aging Biochemistry Bioenergetics Cardiac Cardiac Myocytes Cardiomyopathies Cell Death Cell physiology Cells Cellular biology Communication Data Deacetylase Defect Degenerative Disorder Development Disease Engineering Excision Exhibits Failure Fibrosis Functional disorder Goals Heart Heart Diseases Human Impairment Individual Link Mass Spectrum Analysis Mediating Metabolic Metabolism Mitochondria Mitochondrial Diseases Mitochondrial Proteins Modeling Modification Mus Pathogenesis Pathology Pathway interactions Pattern Phosphate Carriers Physiological Physiology Play Positioning Attribute Post-Translational Protein Processing Process Production Proteins Proteomics Regulation Research Signal Pathway Signal Transduction Sirtuins Stress System Tissue Differentiation Tissues Work arm biological adaptation to stress cyclophilin D design gene therapy in vivo in vivo Model in vivo evaluation innovation insight metabolomics mitochondrial dysfunction mitochondrial metabolism mitochondrial permeability transition pore mouse model new therapeutic target novel overexpression public health relevance response stressor

项目摘要

As critical regulators of cellular metabolism, mitochondria activate various pathways in response to stressors (e.g., aging) and dysfunction (e.g., unfolded proteins). However, little is known about the in vivo pathways mitochondria use to communicate impaired energy production. Mitochondrial energy dysfunction is a hallmark of a range of degenerative diseases affecting tissues with high energy demands, thus understanding how mitochondria respond to energy dysfunction and direct the cellular response to energetic crisis in vivo is critical for the design of targeted strategies to ameliorate these diseases. Here, we will leverage a unique model of in vivo mitochondrial energy impairment that we engineered by inducible deletion of the cardiac mitochondrial phosphate carrier (SLC25A3) in adult mouse cardiomyocytes. This model offers a novel system to model mitochondrial energy impairment in a terminally differentiated tissue with high energy demands. Intriguingly, despite the cardiac disease exhibited by these mice, SLC25A3 deficiency does not engage canonical mitochondrial energy dysfunction pathways like AMPK and ROS signaling, nor is cell death or fibrosis exhibited by deficient hearts. Instead, loss of SLC25A3 in adult hearts causes a striking increase in mitochondria-specific protein acylations, particularly acetylation and malonylation. Acylations are dynamic post-translational modifications derived from metabolic intermediates and subject to removal by sirtuin deacylases. Importantly, acylations harbor the potential to link metabolism to protein functional regulation, while altered acylation is associated with disease pathogenesis. Our preliminary data suggest that, in particular, two aspects of the acylome—the acetylome and the malonylome—are remodeled in response to mitochondrial energy dysfunction. While the acylome is well known to regulate mitochondrial metabolism, our work suggests that the converse is also possible: that mitochondrial energy dysfunction directs acylome remodeling. We hypothesize that acylome modifications represent a mitochondria-intrinsic mechanism to coordinate the cellular response to energy stress. Using the SLC25A3 deletion mice together with cell biology, biochemistry, proteomics, and innovative in vivo gene therapy approaches, we will 1) identify the mechanisms underlying SLC25A3 deletion- mediated acylome remodeling, 2) define how acylations regulate the mitochondrial permeability transition pore cell death pathway, and 3) determine the physiological impact of aberrant acylations on the mitochondrial energy-impaired heart. The proposed studies will provide novel insight on the link between mitochondrial bioenergetics and acylome remodeling and position acylations as an arm of the mitochondrial stress response that is activated upon mitochondrial energy dysfunction. Ultimately, identification of pathways regulating mitochondrial dysfunction will facilitate the development of new therapies targeting mitochondrial energy dysfunction in disease.

作为细胞代谢的关键调节者，线粒体激活各种途径以应对压力（例如衰老）和功能障碍（例如未折叠蛋白质）然而，人们对体内途径知之甚少。线粒体能量功能障碍是一个标志一系列影响高能量需求组织的退行性疾病，从而了解如何线粒体对能量功能障碍做出反应并指导细胞对体内能量危机的反应至关重要在这里，我们将利用一种独特的模型来设计有针对性的策略来改善这些疾病。我们通过诱导性缺失心脏线粒体来设计体内线粒体能量损伤成年小鼠心肌细胞中的磷酸盐载体 (SLC25A3) 该模型提供了一种新的建模系统。有趣的是，具有高能量需求的终末分化组织中的线粒体能量损伤。尽管这些小鼠表现出心脏病，但 SLC25A3 缺陷并不涉及典型的线粒体能量功能障碍途径，如 AMPK 和 ROS 信号传导，也没有表现出细胞死亡或纤维化相反，成人心脏中 SLC25A3 的缺失会导致线粒体特异性显着增加。蛋白质酰化，特别是乙酰化和丙二酰化是动态的翻译后。源自代谢中间体的修饰并可被沉默调节蛋白脱酰酶去除。酰化具有将代谢与蛋白质功能调节联系起来的潜力，而酰化是我们的初步数据表明，特别是与疾病发病机制有关的两个方面。酰基组（乙酰基组和丙二酰基组）根据线粒体能量进行重塑虽然众所周知，酰基组可以调节线粒体代谢，但我们的工作表明，相反的情况也是可能的：线粒体能量功能障碍指导酰基组重塑。酰基组修饰代表了协调细胞响应的线粒体内在机制使用 SLC25A3 缺失小鼠与细胞生物学、生物化学、蛋白质组学和创新的体内基因治疗方法，我们将 1) 确定 SLC25A3 缺失的潜在机制- 介导的酰基组重塑，2) 定义酰化如何调节线粒体通透性过渡孔细胞死亡途径，3) 确定异常酰化对线粒体的生理影响拟议的研究将为线粒体之间的联系提供新的见解。生物能量学和酰基组重塑以及定位酰化作为线粒体应激反应的一个分支最终，在线粒体能量功能障碍时激活其调节途径。线粒体功能障碍将促进针对线粒体能量的新疗法的开发疾病中的功能障碍。