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Mitochondrial dynamics in spermatogonial differentiation

精原细胞分化中的线粒体动力学

基本信息

批准号：
10685938
负责人：
Yuan Wang
金额：
$ 31.43万
依托单位：
MICHIGAN STATE 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：
2022-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685938
关键词：
Acceleration Adult Affect Architecture Area Biology Cell physiology Cells Couples Data Development Developmental Process Equilibrium Event Fluorescence Germ Cells Goals Guanosine Triphosphate Phosphohydrolases Health Impairment In Vitro Infertility Knockout Mice Male Infertility Mammals Metabolic Metabolism Mitochondria Organelles Output Oxidative Phosphorylation Pattern Play Process Reactive Oxygen Species Reproduction Reproductive Medicine Research Respiration Role Series Signal Transduction Somatic Cell Spermatogenesis Spermatogonia Testing Testis Transplantation Undifferentiated cell type conditional knockout insight male male fertility mitochondrial DNA mutation mitochondrial dysfunction mitochondrial fitness mouse model novel novel strategies postnatal real time monitoring sperm cell sperm quality stem cell differentiation stem cell self renewal stem cells

项目摘要

PROJECT SUMMARY Mitochondria are increasingly recognized as key players in a wide range of cellular and developmental processes, such as cell signaling, stem cell self-renewal, and lineage commitment, beyond their canonical roles in metabolism and oxidative phosphorylation. Such functional diversity is largely determined by the cell type- specific mitochondrial features, including mitochondrial number, architecture, distribution, and interaction with other subcellular organelles. These mitochondrial features are tightly regulated via mitochondrial fusion and fission, collectively known as mitochondrial dynamics, the alteration of which will lead to changing mitochondrial functions and activities in a cell type-specific manner, and thus impacts cell fate decision, particularly during development and in stem cell differentiation. We found that upregulated mitochondrial respiration accompanied by increased reactive oxygen species (ROS) is required for postnatal spermatogonial stem cell differentiation. However, such elevated ROS can increase mitochondrial DNA mutations that are deleterious to mitochondrial fitness and cell functions. It remains elusive how stem cells properly balance mitochondrial activities to meet the competing need for increased mitochondrial respiration during differentiation while maintaining mitochondrial fitness. Our pilot data suggest that mitochondria fusion and fission are both upregulated in spermatogonial differentiation, which is essential for sustaining proper male fertility. We thus propose to reveal a novel functional mechanism of how spermatogonial differentiation and germ cell mitochondrial fitness are regulated by concurrently accelerated and properly balanced mitochondrial fusion and fission. To achieve this goal, we will integrate a series of genetically modified mouse models with in vitro spermatogonial differentiation and transplantation approaches. Study findings will fundamentally advance research in both reproductive medicine and mitochondrial biology by explaining how spermatogonial differentiation is regulated via stage-specific mitofusion and fission, thereby unlocking a new area of discovery, namely, how mitochondrial function and health are maintained so in order to support critical and unique events of mammalian development. In addition, by revealing the impacts of mitochondrial dynamics on germ cell mitochondrial fitness, this project will critically inform a novel strategy to treat impaired male fertility due to mitochondrial dysfunctions.

项目总结