Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation

Year: 2021

Authors: Saudino G., Suraci D., Nasta V., Ciofi-Baffoni S., Banci L.

Autors Affiliation: Univ Florence, Magnet Resonance Ctr CERM, I-50019 Sesto Fiorentino, Italy; Univ Florence, Dept Chem Ugo Schiff, I-50019 Sesto Fiorentino, Italy; Consorzio Interuniv Risonanze Magnetiche Metallop, I-50019 Sesto Fiorentino, Italy.

Abstract: Multiple mitochondrial dysfunctions syndrome (MMDS) is a rare neurodegenerative disorder associated with mutations in genes with a vital role in the biogenesis of mitochondrial [4Fe-4S] proteins. Mutations in one of these genes encoding for BOLA3 protein lead to MMDS type 2 (MMDS2). Recently, a novel phenotype for MMDS2 with complete clinical recovery was observed in a patient containing a novel variant (c.176G > A, p.Cys59Tyr) in compound heterozygosity. In this work, we aimed to rationalize this unique phenotype observed in MMDS2. To do so, we first investigated the structural impact of the Cys59Tyr mutation on BOLA3 by NMR, and then we analyzed how the mutation affects both the formation of a hetero-complex between BOLA3 and its protein partner GLRX5 and the iron-sulfur cluster-binding properties of the hetero-complex by various spectroscopic techniques and by experimentally driven molecular docking. We show that (1) the mutation structurally perturbed the iron-sulfur cluster-binding region of BOLA3, but without abolishing [2Fe-2S](2+) cluster-binding on the hetero-complex; (2) tyrosine 59 did not replace cysteine 59 as iron-sulfur cluster ligand; and (3) the mutation promoted the formation of an aberrant apo C59Y BOLA3-GLRX5 complex. All these aspects allowed us to rationalize the unique phenotype observed in MMDS2 caused by Cys59Tyr mutation.

Journal/Review: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Volume: 22 (9)      Pages from: 4848-1  to: 4848-18

More Information: This research was funded by iNEXT-Discovery, grant agreement no. 871037, funded by the Horizon 2020 research and innovation program of the European Commission (to L.B.) and in part by grant no. CRF2018.0920 (to S.C.-B.) from the Fondazione Cassa di Risparmio di Firenze. The article processing charge was funded by Fondi per la ricerca scientifica d’Ateneo Budget 2021.
KeyWords: BOLA3; GLRX5; multiple mitochondrial dysfunctions syndrome; iron- sulfur protein; mitochondria; MMDS2
DOI: 10.3390/ijms22094848

ImpactFactor: 6.208