Off the beaten path(way): Spatiotemporal investigation of protein assemblies controlling mitochondrial metabolism

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Cellular metabolism is the crux of all organismal biology. Therefore, uncovering fundamental knowledge regarding how metabolism is controlled will have far-reaching implications. Metabolic systems are traditionally depicted as linear or circular pathways in textbooks. In reality, these processes are intricately governed by complex, higher-order networks of macromolecules including proteins and lipids. A metabolon is a dynamic cluster of proteins, cofactors, and small molecules that interact to control a metabolic process. Importantly, metabolons are found across multiple biological systems from plants to humans, indicating their fundamental importance in biology. Heme is an essential and conserved biomolecule that is produced by the community of proteins forming the heme metabolon. Heme not only transports oxygen in red blood cells, but it also serves as a catalytic cofactor for proteins governing multiple cellular signaling processes across all kingdoms of life. Thus, determining how proteins assemble and disassemble to control heme metabolon formation will provide insight into production of this critical molecule and also form the basis for studying other key metabolons. Specifically, we will 1) isolate and solve the structure of the heme metabolon, 2) determine dynamics of metabolon formation, and 3) investigate how defects in specific assembly steps alter metabolic output. We will accomplish this by integrating high-resolution cryo-EM with time-resolved proteomics and metabolomics experiments to reveal metabolon dynamics. The combination of these approaches will unite multiple hierarchies of cellular signaling, transforming the static textbook snapshot of metabolism into a 3D movie of a living, breathing metabolic machine. Addressing the fundamental and unknown question of how metabolic networks are controlled via coordinated protein organization will have major impacts in broad areas of research, including cancer progression, diabetes, and the immune response.