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SDHAF1 mutations cause a rare mitochondrial complex II (CII) deficiency, which manifests as infantile leukoencephalopathy with elevated levels of serum and white matter succinate and lactate. Here, we demonstrate that SDHAF1 contributes to iron-sulfur (Fe-S) cluster incorporation into the Fe-S subunit of CII, SDHB. SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region in its C terminus and specifically engages a Fe-S donor complex, consisting of the scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20-HSPA9, through an LYR motif near its N-terminal domain. Pathogenic mutations of SDHAF1 abrogate binding to SDHB, which impairs biogenesis of holo-SDHB and results in LONP1-mediated degradation of SDHB. Riboflavin treatment was found to ameliorate the neurologic condition of patients. We demonstrate that riboflavin enhances flavinylation of SDHA and reduces levels of succinate and Hypoxia-Inducible Factor (HIF)-1α and -2α, explaining the favorable response of patients to riboflavin., (Copyright © 2016 Elsevier Inc. All rights reserved.)

95 Kim JH, Tonelli M, Frederick RO, Chow DC, Markley JL. Specialized Hsp70 chaperone (HscA) binds preferentially to the disordered form, whereas J-protein (HscB) binds preferentially to the structured form of the iron-sulfur cluster scaffold protein (IscU). Abbreviations ABC ATP-binding cassette ABCB7 ABC transporter of the inner mitochondrial membrane, subfamily B, member 7 ACO1 cytosolic aconitase ACP acyl carrier protein ALA aminolaevulinic acid ALAD ALA dehydratase eALAS/ALAS2 erythroid specific 5-aminolevulinate synthase FBXL5 F-box and leucine-rich repeat protein 5 FDX ferredoxin FDXR ferredoxin reductase FECH ferrochelatase Fe-S iron-sulfur FRDA Friedreich ataxia FXN frataxin GLRX5 glutaredoxin 5 HSP70 70-kDa heat shock protein HSP40 40-kD heat shock protein IRE Iron Response Element IRP1/2 Iron Regulatory Protein 1/2 NBD Nucleotide Binding Domain NEF Nucleotide Exchange Factor PLP pyridoxal-phosphate RdRp RNA-dependent RNA polymerase SAM S-adenosylmethionine SBD Substrate Binding Domain TCA tricarboxylic acid UTR untranslated region INTRODUCTION The general pathway of iron sulfur (Fe-S) cluster biogenesis has been gradually elucidated over the years by a combination of genetic and biochemical studies. 126 Pandey AK, Pain J, Dancis A, Pain D. Mitochondria export iron-sulfur and sulfur intermediates to the cytoplasm for iron-sulfur cluster assembly and tRNA thiolation in yeast. In this chapter, we provide an overview of our understanding of iron-sulfur cluster biogenesis in mammalian cells, discuss recent studies that shed light on the molecular interactions that govern iron-sulfur cluster assembly and introduce advances in the understanding of how the transfer complex efficiently engages recipient Fe-S target proteins to deliver a cluster. [Extracted from the article]

The multispanning membrane protein ATG9A is a scramblase that flips phospholipids between the two membrane leaflets, thus contributing to the expansion of the phagophore membrane in the early stages of autophagy. Herein, we show that depletion of ATG9A does not only inhibit autophagy but also increases the size and/or number of lipid droplets in human cell lines and C. elegans. Moreover, ATG9A depletion blocks transfer of fatty acids from lipid droplets to mitochondria and, consequently, utilization of fatty acids in mitochondrial respiration. ATG9A localizes to vesicular-tubular clusters (VTCs) that are tightly associated with an ER subdomain enriched in another multispanning membrane scramblase, TMEM41B, and also in close proximity to phagophores, lipid droplets and mitochondria. These findings indicate that ATG9A plays a critical role in lipid mobilization from lipid droplets to autophagosomes and mitochondria, highlighting the importance of ATG9A in both autophagic and non-autophagic processes. ATG9A is transmembrane autophagic machinery protein that delivers phospholipids to expanding autophagosomes. Mailler et al. show that ATG9A is required to mobilize lipids from lipid droplets for autophagosome expansion as well as mitochondrial fatty acid import and β-oxidation. [ABSTRACT FROM AUTHOR]

The recently solved crystal structures of the human cysteine desulfurase NFS1, in complex with the LYR protein ISD11, the acyl carrier protein ACP, and the main scaffold ISCU, have shed light on the molecular interactions that govern initial cluster assembly on ISCU. Here, we aim to highlight recent insights into iron–sulfur (Fe–S) cluster (ISC) biogenesis in mammalian cells that have arisen from the crystal structures of the core ISC assembly complex. We will also discuss how ISCs are delivered to recipient proteins and the challenges that remain in dissecting the pathways that deliver clusters to numerous Fe–S recipient proteins in both the mitochondrial matrix and cytosolic compartments of mammalian cells. • Iron–sulfur (Fe–S) clusters (ISCs) are metal cofactors involved in multiple, essential cellular processes. • Defined pathways assemble ISCs de novo in mammalian mitochondria and cytosol. • The acyl carrier protein is a component of the core ISC machinery. • Frataxin is an allosteric regulator that accelerates sulfur transfer from NFS1 to ISCU. • A chaperone/cochaperone system facilitates cluster transfer downstream of ISCU. [ABSTRACT FROM AUTHOR]