Understanding metabolic functions of mitochondria in proliferating cells

项目总结 细胞代谢是支持生物能量、生物合成和生物合成的生化过程的集合 标志着生活的需求。虽然大多数人类主要代谢途径的生化成分 我们还没有很好地理解代谢途径是如何被不同地利用来 支持不同蜂窝状态下蜂窝的多样化需求。细胞增殖的激活就是这样一种状态 随着代谢途径活动的实质性变化，然而这些活动的许多机制 新陈代谢变化支持细胞增殖，其破坏的后果尚不清楚。在 细胞新陈代谢的核心是线粒体，这是一个双膜结合的细胞器，起着代谢的作用。 HUB通过提供与胞浆分离的生化隔间，并通过独特的代谢 电子传输链(ETC)提供的能力。虽然最著名的是它在三磷酸腺苷合成中的作用， 来自我们和其他人的研究已经确定，线粒体新陈代谢对于支持细胞是必不可少的。 增殖不依赖于三磷酸腺苷的产生。这些发现颠覆了人们对线粒体的传统看法 仅仅是“动力源”，并强调有必要对线粒体如何支持 细胞功能。我们的工作已经发现，ETC的复合体I通过再生对细胞的增殖至关重要 电子受体，支持氨基酸天冬氨酸的合成。另外，我们的初步数据 发现损伤对ETC的复合体II的代谢影响与复合体I的不同， 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。 复杂性II功能障碍。尽管如此，全面了解人体的代谢作用 线粒体对细胞增殖的过程仍然缺乏。我的研究项目使用了最先进的 描述线粒体过程中断的代谢和功能后果的方法 为了对线粒体中相互关联的代谢途径如何在系统水平上有一个新的理解 支持细胞增殖。值得注意的是，人类线粒体功能的紊乱有非常不同的临床表现。 不同线粒体损伤后果的表现及机制理解 这些进程将支持针对多种疾病的新的、有针对性的治疗方法的开发 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、 老龄化，以及其他。

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.