The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis

Abstract

Mitochondrial fatty acid synthesis (FASII) and iron sulfur cluster (FeS) biogenesis are both vital biosynthetic processes within mitochondria. In this study, we demonstrate that the mitochondrial acyl carrier protein (ACP), which has a well-known role in FASII, plays an unexpected and evolutionarily conserved role in FeS biogenesis. ACP is a stable and essential subunit of the eukaryotic FeS biogenesis complex. In the absence of ACP, the complex is destabilized resulting in a profound depletion of FeS throughout the cell. This role of ACP depends upon its covalently bound 4’-phosphopantetheine (4-PP)-conjugated acyl chain to support maximal cysteine desulfurase activity. Thus, it is likely that ACP is not simply an obligate subunit but also exploits the 4-PP-conjugated acyl chain to coordinate mitochondrial fatty acid and FeS biogenesis.DOI: http://dx.doi.org/10.7554/eLife.17828.001

Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

“…2 C and E). A similar result is observed for mitochondria either depleted in Acp1 (yeast ACP homolog) or with an Acp1 variant incapable of attaching the 4′-PPT prosthetic group (1).…”

“…In the second stage, the heterotrimeric SDA species dimerize to form the stable 4-helix bundle core of the SDA ec architecture. Consistent with this model, NFS1-NFS1 interactions appear to be significantly weaker than IscS-IscS interactions and result in a population of monomeric NFS1 (8,33,58), which has a tendency to aggregate in the absence of either member of the ISD11-ACP pair (1,8). In contrast, the SDA ec dimeric architecture is the predominant species that elutes from a size exclusion column (SI Appendix, Fig.…”

“…However, key, unexplained functional differences exist for the Fe-S assembly complexes that center on the respective cysteine desulfurases. First, two additional proteins, ISD11 and ACP, are required for the stabiliza-tion and function of NFS1 in the eukaryotic system (1,4,5,8,9,27). In contrast, there is no evidence for a role of ACP in prokaryotic Fe-S cluster assembly, and the ACP interactions appear limited to a disulfide bond that would inactivate IscS (45,46).…”

“…The iron-sulfur cluster (ISC) biosynthetic pathway, which is found in most prokaryotes and in the mitochondrial matrix of eukaryotes, is responsible for the synthesis of Fe-S clusters and distribution of these cofactors to the appropriate target proteins. Despite the homology between analogous components of the prokaryotic and eukaryotic ISC pathways, there are key unexplained differences, such as the requirement of the LYR protein ISD11 and acyl carrier protein (ACP) for function in eukaryotic but not prokaryotic ISC systems (1,2).…”

“…However, mitochondrial ACP also functions as a required subunit for respiratory complex I and is predominately associated with the long-chain fatty acid 3-hydroxytetradecanoate (16)(17)(18)(19)(20)(21)(22)(23). More recently, ACP has been identified as an essential functional component of the eukaryotic Fe-S cluster biosynthetic complex (1). Currently, there are no X-ray crystal structures that…”