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.

Public Health Relevance

Toxoplasma gondii is a protozoan parasite that can cause fetal abnormalities and poses a severe risk to immunocompromised individuals, such as HIV patients and organ transplant recipients. No known vaccines or drugs can eradicate persistent T. gondii infections in humans and the parasite is a leading cause of death attributed to foodborne illness in the United States. This research seeks to characterize the parasite's unusual mitochondrial ATP synthase to understand its highly divergent metabolism and identify new targets for the development of anti-parasitic compounds.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K99)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Mcgugan, Glen C
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Whitehead Institute for Biomedical Research
United States
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