The proposed project is a renewal of a previously funded project that was focused on the discovery and characterization of assembly factors for the mitochondrial respiratory complexes. During these studies, we made the unexpected observation that the assembly and activation of those complexes is strictly dependent upon the rather poorly understood mitochondrial fatty acid synthesis (mtFAS) pathway. When this pathway is active, it synthesizes acyl chains that are covalently attached to the Acp1 scaffold protein, which when acylated binds and activates the LYR family of regulators that are required for respiratory complex assembly and iron-sulfur cluster biogenesis. We further demonstrated that the activity of mtFAS and the acylation state of Acp1 is sensitive to the availability of mitochondrial acetyl-coA, which is also the principal fuel for mitochondrial oxidative metabolism. Therefore, we hypothesize that this system provides an elegant mechanism to enable the coupling of assembly and activation of the mitochondrial respiratory system with the availability of substrates for that system. To test this hypothesis and better define the underlying mechanisms, we propose the follow aims.
Aim 1) Define the role of mtFAS in the regulation of iron-sulfur cluster synthesis.
Aim 2) Define the mtFAS and LYR-dependent regulation of OXPHOS biogenesis.
Aim 3) Discover and characterize novel targets of mtFAS and ACP regulation. We propose that a better understanding of mtFAS and how it regulates activation of Acp1 targets could lead to therapeutic approaches to boost and optimize mitochondrial respiration.
We have discovered that the mitochondrial system for making fatty acids has an unexpected role in building and activating the machinery that is required to consume substrates and convert them to usable energy to fuel cellular functions. We hypothesize that this serves as a means whereby that machinery can be optimally coordinated with the availability of energy substrate. This is made possible because acetyl-CoA is the major input into both processes. We propose to use yeast as a model system to understand the regulation and function of this novel regulatory system, which will provide a foundation for future work to understand how this works in mammals and whether it may be a therapeutically tractable target for intervention in mitochondria-related diseases.
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