Abstract
Mitochondrial proteins carrying iron-sulfur (Fe-S) clusters are involved in essential cellular pathways such as oxidative phosphorylation, lipoic acid synthesis, and iron metabolism. NFU1, BOLA3, IBA57, ISCA2, and ISCA1 are involved in the last steps of the maturation of mitochondrial [4Fe-4S]-containing proteins. Since 2011, mutations in their genes leading to five multiple mitochondrial dysfunction syndromes (MMDS types 1 to 5) were reported. The aim of this systematic review is to describe all reported MMDS-patients. Their clinical, biological, and radiological data and associated genotype will be compared to each other. Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy. Diagnosis could be suggested by high lactate, pyruvate, and glycine levels in body fluids. Genetic analysis including large gene panels (Next Generation Sequencing) or whole exome sequencing is needed to confirm diagnosis.
Highlights
The methodology we haveWe adopted was this review by highlighting the essential roles of proteins in human cells and their based on Pubmed searches using “multiple mitochondrial dysfunction syndrome”, biogenesis pathways.“IBA57”, “ISCA2”, and “ISCA1” as keywords
[2Fe-2S] 2+ cluster is built de novo on the scaffold protein ISCU by assembling two Fe2+ ions imported into the mitochondrion by the inner mitochondrial membrane transporters, called mitoferrins [23], and two sulfide ions produced from the desulfuration of the cysteines by the NFS1-ISD11-ACP complex [24,25,26]
Supplementary analysis on tissues from patients with MMDS1 found that pyruvate dehydrogenase (PDH) and GCS impairment was secondary to lipoic acid synthesis disruption
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Conserved across all kingdoms of life, iron-sulfur (Fe-S) clusters are ancient prosthetic groups They are found in a variety of proteins involved in diverse essential cellular pathways such as the Krebs cycle, the mitochondrial respiratory chain (RC), or in DNA replication and repair [1]. Maturation of the mitochondrial [2Fe-2S]-containing proteins can directly proceed from GLRX5, while the maturation of the [4Fe-4S]-containing proteins requires supplementary steps with the biosynthesis of the [4Fe-4S] cluster and its delivery to mitochondrial [4Fe-4S] proteins [2,3] These last steps involve six proteins, namely NUBPL (formerly named IND1), NFU1, BOLA3, IBA57, ISCA2, and ISCA1, whose functions are poorly known and are currently the subject of intense research [4,5] (Figure 1). Biomedicines 2021, 9, x FOR PEER REVIEW proteins, which results in a deficiency of mitochondrial respiratory complexes and of the impaired function of lipoic-acid-dependent enzymes
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