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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Van Vranken, Jonathan G; Nowinski, Sara M; Clowers, Katie J et al. (2018) ACP Acylation Is an Acetyl-CoA-Dependent Modification Required for Electron Transport Chain Assembly. Mol Cell 71:567-580.e4
Tanner, Jason M; Bensard, Claire; Wei, Peng et al. (2017) EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma. Mol Cancer Res 15:1517-1530
Fetherolf, Morgan M; Boyd, Stefanie D; Taylor, Alexander B et al. (2017) Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site. J Biol Chem 292:12025-12040
Schell, John C; Wisidagama, Dona R; Bensard, Claire et al. (2017) Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol 19:1027-1036
Dwight, Trisha; Na, Un; Kim, Edward et al. (2017) Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma. BMC Cancer 17:497
Cory, Seth A; Van Vranken, Jonathan G; Brignole, Edward J et al. (2017) Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proc Natl Acad Sci U S A 114:E5325-E5334
Melber, Andrew; Na, Un; Vashisht, Ajay et al. (2016) Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients. Elife 5:
Melber, Andrew; Winge, Dennis R (2016) Inner Secrets of the Respirasome. Cell 167:1450-1452
Kim, Hyung J; Jeong, Mi-Young; Parnell, Timothy J et al. (2016) The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria. J Biol Chem 291:17417-26
Van Vranken, Jonathan G; Jeong, Mi-Young; Wei, Peng et al. (2016) The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis. Elife 5:

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