BOLA3 and NFU1 Link Mitoribosome Iron–Sulfur Cluster Assembly to Multiple Mitochondrial Dysfunctions Syndrome

Authors

Hui Zhong, University of Miami Miller School of Medicine
Alexandre Janer, McGill University
Oleh Khalimonchuk, University of Nebraska-LincolnFollow
Hana Antonicka, McGill University
Eric A. Shoubridge, McGill University
Antoni Barrientos, University of Miami Miller School of Medicine

Document Type

Article

Date of this Version

10-12-2023

Citation

Nucleic Acids Research (2023) 51: 11,797–11,812

doi: 10.1093/nar/gkad842

Comments

Open access

Abstract

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 e xpression 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, w e 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.