Molecular and Metabolic Adaptations of Intracellular Parasitism

/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. Project Number: 1R35GM161383-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Paul Sigala | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $423,500 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260291