BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Iron-Sulfur Proteins*/chemistry ; Mitochondrial Ribosomes*/metabolism ; Mitochondrial Diseases*/metabolism; Humans ; Carrier Proteins/metabolism ; Iron/metabolism ; Methyltransferases/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Sulfur/metabolism

The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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R35 GM118141 United States GM NIGMS NIH HHS; R35 GM131701 United States GM NIGMS NIH HHS; FRN178373 Canada CAPMC CIHR; GM118141 United States GM NIGMS NIH HHS

0 (Carrier Proteins)
E1UOL152H7 (Iron)
0 (Iron-Sulfur Proteins)
0 (ISCA1 protein, human)
EC 2.1.1.- (Methyltransferases)
EC 2.1.1.- (METTL17 protein, human)
0 (Mitochondrial Proteins)
0 (NFU1 protein, human)
70FD1KFU70 (Sulfur)
0 (BolA3 protein, human)

Multiple Mitochondrial Dysfunctions Syndrome

Date Created: 20231012 Date Completed: 20231130 Latest Revision: 20241014

20241014

PMC10681725

10.1093/nar/gkad842

37823603