Molecular and metabolic adaptations of intracellular parasitism

The National Institute of General Medical Sciences awarded the University of Utah $885,637 in project grant funding on March 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859).

The University of Utah, through its Office of Sponsored Projects Division, will conduct a five-year investigation into the molecular and metabolic adaptations that enable apicomplexan parasites—particularly Plasmodium species that cause malaria—to survive and replicate within host cells. The research focuses on divergent acyl carrier protein (ACP) functions at the intersection of mitochondrial and apicoplast metabolism in these organisms. Specifically, the investigator will elucidate how Plasmodium parasites, despite losing conventional mitochondrial fatty acid synthesis, retain a specialized acyl carrier protein essential for stabilizing iron-sulfur cluster assembly and how a second ACP protein in the apicoplast interacts with pyruvate kinase enzymes in ways not seen in other eukaryotes. The work builds on prior discoveries funded through the Maximizing Investigators' Research Award (MIRA) program and aims to identify pathogen-specific metabolic vulnerabilities that could inform drug development.

Performance will occur in Salt Lake City, Utah, with a period of performance from March 1, 2026, through December 31, 2030.

Abstract

The metabolic functions of organelles like mitochondria are central to eukaryotic cells, including humans and apicomplexan parasites that infect human cells. These protozoan microbes diverged from animals and fungi early in cellular evolution and acquired unusual molecular and metabolic adaptations that specialize them to grow inside animal cells. These adaptations include altered mitochondrial functions and acquisition of a non- photosynthetic plastid organelle called the apicoplast. Our long-term goal is to understand the metabolic mechanisms that specialize these early-diverging eukaryotes for intracellular growth and survival. Unraveling these molecular mechanisms will elucidate new molecular paradigms for organelle metabolism, shed light on the metabolic adaptations that distinguish intracellular parasites and humans, and identify pathogen-specific vulnerabilities. In mira-funded work, we discovered that plasmodium parasites, unlike most eukaryotes, have lost mitochondrial fatty acid synthesis (fasii) but retain a divergent acyl carrier protein (macp) that cannot tether acyl groups. Nevertheless, this unusual macp is essential for stabilizing the FE-s cluster assembly complex via a divergent molecular interface that decouples mitochondrial FE-s and fatty acid metabolism. We also discovered that these organisms retain a second essential ACP protein within the apicoplast (aacp), where IT has a critical function independent of the fasii pathway in this organelle and involves an unprecedented association with a key pyruvate kinase enzyme that appears to require the 4-phosphopantetheine group on aacp. Our five-year objective is to unravel the molecular mechanisms of divergent ACP functions at the nexus of mitochondrial and apicoplast metabolism in plasmodium. In the mitochondrion, we will elucidate a second critical role for macp in maturation of the rieske FE-s protein that has mechanistic features distinct from human mitochondria. We have also identified a parasite-specific LYR-family adapter protein that binds macp and whose function in mitochondrial metabolism we propose to unravel. In the apicoplast, we will dissect aacp association with pyruvate kinase and test a model that this interaction plays a key regulatory role to sense host nutritional status and couple IT to variable pyruvate kinase stability that controls broad apicoplast metabolism. These studies will deeply advance understanding of metabolic mechanisms within the plasmodium mitochondrion and apicoplast organelles that underpin evolutionary specialization for intracellular parasitism and lay a groundwork to support future treatment strategies.