Investigating the Mitochondrial-Derived Compartment Pathway

项目概要/摘要 线粒体是细胞代谢的中心枢纽，它们的功能障碍与许多与年龄相关的疾病有关， 代谢紊乱。作为细胞能量产生和代谢物生物合成的主要来源，线粒体 不断吸收和释放各种细胞内营养物质。这使得线粒体容易受到 在与代谢超负荷相关的疾病中经常观察到的营养浓度变化。的确， 我们实验室最近的工作表明，线粒体对细胞内氨基酸水平的升高特别敏感， 氨基酸毒性是与年龄相关的线粒体衰退的关键驱动因素。向前看，一个大 我们实验室的目标是了解氨基酸升高损害线粒体功能的机制， 确定保护线粒体免受氨基酸应激的途径。在上一个项目期间，我们 确定了氨基酸半胱氨酸在调节线粒体呼吸中的关键作用，并发现了一种新的 细胞结构，称为线粒体衍生的复合体（MDC），保护细胞免受有害影响 过量的氨基酸。我们目前的数据表明，MDCs是动态的细胞器样结构， 由线粒体响应细胞内氨基酸升高而产生。在形成时，MDC选择性地 排序和删除线粒体载体超家族的蛋白质，代谢物转运的关键介质， 线粒体内膜，远离线粒体网络的其余部分。MDC是保守的， 酵母对人类的影响，MDC途径的缺失使细胞对氨基酸过载敏感。这些结果 导致了我们目前的工作模型，MDC的形成代表了一种新的机制， 线粒体营养转运蛋白响应细胞代谢供应的变化。目前我们的 对MDCs在细胞代谢中的生物发生、营养调节和作用的理解还远未完成。 在下一个项目期间，我们将在酵母和哺乳动物系统中阐明机制， 参与MDC生物发生的机制，识别控制MDC激活的营养线索和传感器，以及 确定该途径在线粒体和细胞代谢中的作用。因为线粒体代谢物 转运蛋白是细胞代谢的关键调节点，我们预计阐明其功能 新的细胞途径将对我们理解线粒体生理及其作用产生重大影响 在人类疾病中。

PROJECT SUMMARY/ABSTRACT Mitochondria are central hubs of cellular metabolism, and their dysfunction is linked to a host of age-related and metabolic disorders. As a major source of cellular energy production and metabolite biosynthesis, mitochondria continually take up and release a variety of intracellular nutrients. This renders mitochondria vulnerable to changes in nutrient concentrations frequently observed in disorders associated with metabolic overload. Indeed, recent work from our lab showed that mitochondria are uniquely sensitive to elevations in intracellular amino acid load, and that amino acid toxicity is a key driver of age-related mitochondrial decline. Moving forward, a major goal of our lab is to understand mechanisms by which elevated amino acids impair mitochondrial function, and identify pathways that protect mitochondria from amino acid stress. In work during the last project period, we identified a key role for the amino acid cysteine in regulating mitochondrial respiration, and uncovered a new cellular structure, called the Mitochondrial-Derived Compartment (MDC), that protects cells from harmful effects of excess amino acids. Our current data suggests that MDCs are dynamic, organelle-like structures that are generated from mitochondria in response to intracellular amino acid elevation. Upon formation, MDCs selectively sort and remove proteins of the mitochondrial carrier superfamily, key mediators of metabolite transport across the mitochondrial inner membrane, away from the rest of the mitochondrial network. MDCs are conserved from yeast to humans, and loss of the MDC pathway renders cells susceptible to amino acid overload. These results have led to our current working model that MDC formation represents a new mechanism to acutely regulate mitochondrial nutrient transporters in response to changes in cellular metabolic supply. Currently, our understanding of the biogenesis, nutrient regulation, and role of MDCs in cellular metabolism is far from complete. During the next project period, we will work in both yeast and mammalian systems to elucidate mechanisms and machinery involved in MDC biogenesis, identify nutrient cues and sensors that control MDC activation, and determine the role of this pathway in mitochondrial and cellular metabolism. Because mitochondrial metabolite transporters are key regulatory points of cellular metabolism, we anticipate that elucidating the function of this new cellular pathway will have significant impact on our understanding of mitochondrial physiology and its role in human disease.