The biosynthesis of Fe-S clusters is a vital process involving the delivery of elemental iron and sulfur to scaffold proteins via molecular interactions that are still poorly defined. Furthermore, molecular modeling suggests that two subunits of the cysteine desulfurase, Nfs1, may bind symmetrically on top of two adjacent Isu1 trimers in a manner that creates two putative [2Fe-2S] cluster assembly centers. In each center, conserved amino acids known to be involved in sulfur and iron donation by Nfs1 and Yfh1, respectively, are in close proximity to the Fe-S cluster-coordinating residues of Isu1. We suggest that this architecture is suitable to ensure concerted and protected transfer of potentially toxic iron and sulfur atoms to Isu1 during Fe-S cluster assembly.

Objectives: To assess the etiologies and outcomes of patients with secondary hemophagocytic lymphohistiocytosis in the PICU. Design: Prospective observational cohort study. Setting: A single PICU at a pediatric tertiary hospital in Hanoi, Vietnam. Patients: Pediatric patients meeting the criteria for secondary hemophagocytic lymphohistiocytosis. Interventions: None. Measurements and Main Results: Between June 2017 and May 2018, 25 consecutive patients with a mean (sd) age of 23.3 months (21.6 mo) were included. Collected variables included etiologies of hemophagocytic lymphohistiocytosis and clinical and laboratory findings at admission. The Pediatric Index of Mortality 2 score at admission was calculated. Outcomes were death and multiple organ dysfunction. The severity of multiple organ dysfunction was assessed by the Pediatric Logistic Organ Dysfunction 2 score. The mean (sd) Pediatric Index of Mortality 2 predicted mortality rate was 5.6% (7.6%). Cytomegalovirus and Epstein-Barr virus coinfections (60%) were the most common suspected etiology of hemophagocytic lymphohistiocytosis. Other etiologies included Epstein-Barr virus sole infections (20%), cytomegalovirus sole infections (16%), and one unknown cause (4%). Multiple organ dysfunction (excluding hematologic failure) was found in 22 patients (88%) with death occurring in 14 patients (56%). The mean (sd) Pediatric Logistic Organ Dysfunction 2 predicted mortality rate among patients with multiple organ dysfunction was 11.9% (11.2%). Despite having lower Pediatric Index of Mortality 2 predicted mortality rates at admission, Epstein-Barr virus-cytomegalovirus coinfection cases with multiple organ dysfunction had slightly greater Pediatric Logistic Organ Dysfunction 2 predicted mortality rates than Epstein-Barr virus sole infection cases with multiple organ dysfunction: 12.2% (10.5%) versus 11.3% (11.0%). However, these rates were lower than cytomegalovirus sole infection cases with multiple organ dysfunction (14.4% [16.3%]). Area under the curve values for Pediatric Index of Mortality 2 and Pediatric Logistic Organ Dysfunction 2 were 0.74 (95% CI, 0.52–0.95) and 0.78 (95% CI, 0.52–1.00), respectively, suggesting that both scales were fair to good at predicting mortality. Conclusions: Viral infections, particularly Epstein-Barr virus-cytomegalovirus coinfections, were a common cause of secondary hemophagocytic lymphohistiocytosis. The implication of these coinfections on the clinical course of hemophagocytic lymphohistiocytosis needs to be delineated.

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Early studies of the bacterial Fe-S cluster assembly system provided have structural details for how the scaffold protein and the cysteine desulfurase interact. This study and an additional study on the yeast and human systems elucidated a conserved mechanism for sulfur donation, but did not provide any conclusive insights into the mechanism for iron delivery from the iron donor frataxin to the scaffold. We previously showed that oligomerization is a mechanism by which yeast frataxin (Yfh1) can promote assembly of the core machinery for Fe-S cluster synthesis both in vitro and in cells, such that the scaffold protein Isu1 can bind to Yfh1 independent of the presence of the cysteine desulfurase Nfs1. Herein, in the absence of Yfh1, Isu1 was found to exist in two forms: one mostly monomeric with limited tendency to dimerize and other with a strong propensity to oligomerize. The monomeric form is stabilized by zinc, and the loss of zinc promotes formation of a dimer and higher order oligomers; however, upon binding to oligomeric Yfh1, both forms take on a similar symmetrical trimeric configuration that places the Fe-S cluster coordinating residues of Isu1 in close proximity to iron-binding residues of Yfh1. This configuration is suitable for the docking of Nfs1 in a manner that provides a structural context for coordinate iron and sulfur donation to the scaffold. Moreover, distinct structural features suggest that under physiological conditions, the zinc-regulated abundance of monomeric vs. oligomeric Isu1 yields [Yfh1]•[Isu1] complexes with different Isu1 configurations that afford unique functional properties for Fe-S cluster assembly and delivery.

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