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.

项目概要细胞代谢是支持生物能量、生物合成和代谢的生化过程的集合。而大多数主要人类代谢途径的生化成分具有生命的信号需求。虽然已经被定义，但我们还没有深入了解代谢途径如何被差异化地利用支持细胞在不同细胞状态下的不同需求，细胞增殖的激活就是这样一种状态。代谢途径活动发生了重大变化，但是这些变化的许多机制代谢变化支持细胞增殖，而其破坏的后果仍然未知。细胞代谢的核心是线粒体，它是一种双层膜结合的细胞器，充当代谢通过提供与细胞质分离的生化区室并通过独特的代谢电子传递链 (ETC) 提供的功能虽然以其在 ATP 合成中的作用而闻名，我们和其他人的研究已经确定线粒体代谢对于支持细胞至关重要这些发现颠覆了线粒体的传统观点。仅仅作为“动力源”，并强调需要对线粒体如何支持有一个新的、全面的理解我们的工作已确定 ETC 复合物 I 通过再生对细胞增殖至关重要。电子受体，支持氨基酸天冬氨酸的合成此外，我们的初步数据。发现 ETC 复合物 II 损伤的代谢影响与复合物 I 的代谢影响不同，我们发现了一种新的、氧化还原驱动的线粒体代谢途径，是细胞增殖所必需的尽管如此，对复杂II功能障碍的代谢贡献有全面的了解。我的研究计划使用最先进的技术，但线粒体对细胞增殖的过程仍然缺乏。描述线粒体过程中断的代谢和功能后果的方法获得关于线粒体中相互关联的代谢途径如何的新的、系统水平的理解值得注意的是，人类线粒体功能的破坏具有高度多样化的临床症状。表现以及对不同线粒体损伤后果的机械理解过程将支持针对许多疾病开发新颖的、有针对性的治疗方法与线粒体失调有关，包括先天性代谢错误、癌症、神经退行性变、衰老等。