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

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Summary:

In this paper, the authors find that in addition to its role as a scaffold for acyl chain elongation, Acp1 (S. cerevisiae homolog) is also a subunit of the ISU complex involved in FeS biogenesis, a result that was also recently reported in human cells in the context of a large scale interactome study. Using genetic tools in yeast, the authors demonstrate loss of the ISU complex and FeS biogenesis (specifically OXPHOS complexes II and III subunits), as well as loss of a lipoic acid-containing PDH subunit as expected. Cytosolic FeS-containing systems were also affected and convincingly demonstrated (qPCR of transcripts known to be upregulated upon impaired mito FeS synthesis, activity of cytosolic sulfite reductase). Turnover of mammalian ISU subunits upon knockdown of NDUFAB1 (human ACP) was also demonstrated, suggesting the phenomenon is conserved (however more work will be needed to establish this given the complexities of the dually and now potentially triple localized human ACP, although this is probably out of the scope of this short report). Finally, using a mutant of ACP unable to conjugate the acyl chain, the authors demonstrate its importance in lipoic acid synthesis as expected, as well as FeS biogenesis. Interestingly, cells expressing only ACP unable to conjugate the acyl chain remain viable, suggesting the essentiality of ACP is in fact due to its involvement in FeS biogenesis. Knockout of the enzyme conjugating the acyl chain to ACP had a similar effect. The authors also found that overexpression of a mitochondrial ion transporter and to a lesser extent another subunit of the ISU complex, restored the levels of the ISU complex (and substrates). Taken together the assumption is that the stability of the ISU complex is being impaired or increased respectively, and also that the acyl chain has a primarily structural role in the ISU complex rather than a functional one. This is very nicely controlled report demonstrating a totally unexpected role for ACP in FeS biogenesis.

Essential revisions:

The reviewers felt that the paper is very strong but there was a consensus that a stronger caveat should be made with respect to the possible role of the acyl carrier group, based on the phenotype of the S82 mutant. It is possible that there is exclusively a structural role but that there is a structural defect in the S82 mutant that reduces folding/assembly to some extent. This would require a textual change.