Understanding the highly divergent mitochondrial ATP synthase in T. gondii

了解弓形虫中高度分化的线粒体 ATP 合酶

• 批准号: 10056323
• 负责人: Diego Huet
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056323
• 关键词: ATP Synthesis Pathway; Antiparasitic Agents; Base Sequence; Biochemical; Biogenesis; Biology; Carbon; Cause of Death; Cell physiology; Cells; Cessation of life; Co-Immunoprecipitations; Complement; Complex; Coupled; Couples; Crista ampullaris; DNA; Defect; Development; Dissection; Environment; Enzymes; Equipment and supply inventories; Eukaryota; Eukaryotic Cell; Generations; Genes; Genetic; Genome; Goals; HIV; Human; Immunocompromised Host; Individual; Life Cycle Stages; Life Style; Lipids; Maintenance; Mass Spectrum Analysis; Measures; Membrane Potentials; Mentors; Metabolic; Metabolism; Methods; Microscopy; Mitochondria; Mitochondrial Proton-Translocating ATPases; Modeling; Molecular; Names; Organ Transplantation; Organelles; Oxidative Phosphorylation; Parasites; Parasitology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological; Physiology; Plasmodium; Plasmodium falciparum; Play; Population; Post Translational Modification Analysis; Post-Translational Protein Processing; Process; Proteins; Proteomics; Proton-Motive Force; Protons; Reaction; Research; Respiration; Risk; Role; Source; Structure; Techniques; Time; Toxoplasma gondii; Toxoplasmosis; Transplant Recipients; Tumor stage; United States; Vaccines; conditional mutant; environmental change; experience; extracellular; fetal; fitness; foodborne illness; gene discovery; genome-wide; human pathogen; interest; loss of function; metabolome; metabolomics; mitochondrial genome; mitochondrial metabolism; mutant; neglect; novel

7. PROJECT SUMMARY/ABSTRACT Apicomplexan parasites are among the most common and deadly pathogens of humans. For example, T. gondii infects an estimated 25% of the world's population and Plasmodium spp. contributes to nearly one million deaths each year. A key feature of apicomplexans is their ability to survive in a wide variety of environments as they transfer between hosts or enter and exit host cells. The wide range of cells that these parasites can infect reflects the plasticity of their metabolism, which undoubtedly evolved to allow their survival within the diverse host niches they colonize. Mitochondria are the metabolic hubs of the eukaryotic cell. Reactions within the mitochondria must adapt to the available carbon sources and the cellular energetic needs. Apicomplexan parasites possess a single mitochondrion responsible for these processes. Within the mitochondria, the ATP synthase couples the proton- motive force generated by respiration to ATP synthesis and thus plays a key role in metabolic plasticity. However, sequence-based searches have failed to identify several key subunits of the ATP synthase in the genome of apicomplexans. This exemplifies how the ATP synthase, and mitochondrial function in general, are poorly understood aspects of apicomplexan biology. The goal of this proposal is to identify the missing components of the apicomplexan ATP synthase by using T. gondii as a model and understand the role that this enzyme plays in mitochondrial physiology. The proposed project also aims to isolate mitochondria from T. gondii, paving the way to an unprecedented inventory of its proteins, DNA, and lipids. Characterizing the ATP synthase as well as determining a mitochondrial metabolome will be of broad interest to the fields of molecular parasitology. These studies will open new perspectives on the divergent apicomplexan metabolism and provide opportunities to develop urgently needed anti-parasitic therapies.

7. 项目总结/文摘