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Understanding metabolic functions of mitochondria in proliferating cells

了解增殖细胞中线粒体的代谢功能

基本信息

批准号：
10670385
负责人：
Lucas Bryan Sullivan
金额：
$ 44万
依托单位：
FRED HUTCHINSON CANCER CENTER
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：
2022-08-01 至 2027-05-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY Cell metabolism is the collection of biochemical processes that support the bioenergetic, biosynthetic, and signaling demands of life. While the biochemical composition of most major human metabolic pathways have been defined, we do not yet have a strong understanding of how metabolic pathways are differentially utilized to support the diverse needs of cells across cell states. Activation of cell proliferation is one such state that comes with substantial changes to metabolic pathway activities, however many of the mechanisms by which these metabolic changes support cell proliferation, and the consequences of their disruption, remain unknown. At the heart of cell metabolism is the mitochondrion, a double membrane bound organelle that serves as a metabolic hub by providing a separate biochemical compartment from the cytosol and through the unique metabolic capabilities afforded by the electron transport chain (ETC). While most famous for its role in ATP synthesis, studies from us and others have determined that mitochondrial metabolism is essential for supporting cell proliferation independent of ATP production. These findings have upended the traditional view of mitochondria as mere “powerhouses” and underscore the need for a new, holistic understanding of how mitochondria support cell functions. Our work has identified that complex I of the ETC is critical for cell proliferation by regenerating electron acceptors, which support the synthesis of the amino acid aspartate. In addition, our preliminary data uncover that the metabolic effects of impairments to complex II of the ETC are distinct from those of complex I, and we identify a novel, redox-driven mitochondrial metabolic pathway necessary for cell proliferation upon complex II dysfunction. Nevertheless, a comprehensive understanding of the metabolic contributions of mitochondrial processes to cell proliferation remains lacking. My research program uses state-of-the-art approaches to delineate the metabolic and functional consequences of disruptions to mitochondrial processes to gain a new, systems level understanding of how the interconnected metabolic pathways in mitochondria support cell proliferation. Notably, disruptions to mitochondrial function in humans have highly diverse clinical manifestations and so mechanistic understanding of the consequences of impairments to different mitochondrial processes will support the development of novel, targeted therapeutic approaches for the many diseases associated with mitochondrial dysregulation, including inborn errors of metabolism, cancer, neurodegeneration, aging, and others.

项目摘要细胞代谢是支持生物能、生物合成和代谢的生物化学过程的集合。发出生命的信号。虽然大多数主要的人体代谢途径的生化组成虽然已经被定义，但我们还没有很好地理解代谢途径是如何被差异化利用的，支持不同细胞状态下细胞的不同需求。细胞增殖的激活就是这样一种状态，代谢途径活动发生了实质性变化，然而，代谢变化支持细胞增殖，其破坏的后果仍然未知。在细胞代谢的心脏是线粒体，一种双膜结合的细胞器，作为代谢的核心。通过提供与细胞质分离的生化隔室，并通过独特的代谢途径，电子传递链（ETC）提供的能力。虽然最著名的是它在ATP合成中的作用，我们和其他人的研究已经确定，线粒体代谢对于支持细胞生长至关重要。增殖不依赖于ATP的产生。这些发现颠覆了线粒体的传统观点仅仅是“发电站”，并强调需要一个新的，全面的理解线粒体如何支持细胞功能。我们的工作已经确定ETC的复合物I通过再生对细胞增殖至关重要电子受体，其支持氨基酸天冬氨酸的合成。此外，我们的初步数据显示，发现ETC复合物II损伤的代谢效应与复合物I的代谢效应不同，我们确定了一种新的，氧化还原驱动的线粒体代谢途径，复合体II功能障碍。然而，全面了解代谢的贡献，线粒体过程对细胞增殖的影响仍然缺乏。我的研究项目使用最先进的描述线粒体过程破坏的代谢和功能后果的方法为了获得一个新的，系统水平的理解，如何在线粒体相互关联的代谢途径，支持细胞增殖。值得注意的是，人类线粒体功能的破坏具有高度多样的临床意义。表现，因此对不同线粒体损伤后果的机械理解这些过程将支持开发针对许多疾病的新型靶向治疗方法，与线粒体失调相关，包括先天性代谢缺陷，癌症，神经变性，老化，以及其他。