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剂，线粒体会激活各种途径，以应对应激源（例如，衰老）和功能障碍（例如，展开的蛋白质）。但是，对体内途径知之甚少线粒体用于传达能源生产受损的情况。线粒体能量功能障碍是标志一系列影响高能量需求组织的退化性疾病，从而了解线粒体对能量功能障碍的反应并指导体内对能量危机的细胞反应至关重要为了设计有针对性的策略来改善这些疾病。在这里，我们将利用一个独特的模型我们通过心脏线粒体诱导缺失设计的体内线粒体能量障碍成年小鼠心肌细胞中的磷酸盐载体（SLC25A3）。该模型提供了一个新颖的系统来建模在终极分化的组织中，线粒体能量损伤具有高能量的需求。有趣的是，尽管这些小鼠暴露了心脏疾病，但SLC25A3缺乏症不吸引经典线粒体能量功能障碍途径（如AMPK和ROS信号传导）也不暴露于细胞死亡或纤维化由于心脏不足。相反，成人心脏中SLC25A3的损失导致线粒体特异性的罢工增加蛋白质酰化，尤其是乙酰化和误导化。酰基化是动态的翻译后源自代谢中间体的修饰，并由Sirtuin脱酰酶去除。重要的是，酰基化具有将代谢与蛋白质功能调节联系起来的潜力，而改变的酰化为与疾病发病机理有关。我们的初步数据表明，特别是酰基 - 乙酰基组和丙度胶 - 对线粒体能量进行了重塑功能障碍。虽然众所周知酰基体可以调节线粒体代谢，但我们的工作表明也可以进行匡威：线粒体能量功能障碍指导酰基团重塑。我们假设该酰基体的修饰代表了线粒体内神经机制，以协调细胞反应能量应力。使用SLC25A3缺失小鼠以及细胞生物学，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缺失的机制 - 介导的酰基重塑，2）定义酰基化如何调节线粒体通透性过渡孔细胞死亡途径和3）确定异常酰化对线粒体的物理影响能量障碍的心脏。拟议的研究将为线粒体之间的联系提供新的见解生物能和酰基重塑和位置酰基化作为线粒体应力反应的臂在线粒体能量功能障碍时被激活。最终，识别路径调节线粒体功能障碍将促进针对线粒体能量的新疗法的发展疾病功能障碍。