Thursday, November 21, 2024
11/21/2024
Project Summary The emergence of eukaryotes from an exclusively prokaryotic biosphere, a momentous event that charted a divergent course for life on Earth, coincided with symbiotic adoption of mitochondria. The complexity of eukaryotes could not have existed and evolved but for the energy economy supported by mitochondrial physiology. Given the strong evidence for the monophyletic origin of mitochondria, it is probable that all extant mitochondria can trace their origin to that singular primordial event at the dawn of eukaryotes. Yet, the evolution has led to tremendous variety of mitochondria, their genomes, their regulation, and their functions, which are as diverse as the organisms they reside in We are interested in understanding mitochondrial functions in malaria parasites, pathogens that extract a tremendous toll from the health and wellbeing of vast multitudes. Over 30 years ago, our group discovered the unusual mtDNA in Plasmodium that encoded just 3 mitochondrial electron transport chain (mtETC) subunits and ribosomal RNA in fragmented and scrambled pieces. With the long-term support of this grant award, we have elucidated many aspects of mitochondrial functions in malaria parasites, showing the organelle to be the target for antimalarial drugs currently in use as well as those in development. We have shown which of the canonical mitochondrial functions are critical in blood stages and which are essential only for the insect stages of the parasite. We have also identified unique and essential features of Plasmodium mitochondrion using genetic and proteomic investigations. In recent years, our efforts have been joined by other investigators working to understand the mitochondrion in apicomplexan parasites. Together, we are at a stage when many of the mysteries surrounding this organelle in Plasmodium and Toxoplasma are being addressed with the application of powerful new approaches. For the next funding period, we are proposing to conduct studies that would bring us closer to answering some of the most critical questions remaining about mitochondrial functions in malaria parasites. These include potential dual function of Complex III, understanding the nature of mitochondrial complexes, and the unusual structural features of mitochondria in asexual and sexual stages of the parasite. As before, the work we are proposing will be carried out by an outstanding collaborative team including a consortium arrangement. Specifically, we will investigate an essential mitochondrial protein an human orthologue of which has been shown to have multiple functions in mitochondrial biogenesis and metabolism. These studies will use biochemical and metabolomic approaches in addition to genetic manipulations. In a consortium arrangement, we will use cryo-electron tomography to study in situ unusual features of mitochondrial structures in asexual and sexual stages of P. falciparum as well as consequences of genetic disruptions of a select number of mitochondrial functions. We will also explore a potential secondary function of the mtETC Complex III as a reason to maintain mtDNA even in mtETC independent parasites.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
