Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing
Beatrice Bargagna1,2, Tommaso Staderini1,2, Steven H Lang3,4
1Department of Chemistry, University of Florence, Via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy.
Abstract:
Multiple mitochondrial dysfunctions syndrome type 3 (MMDS3) is a rare autosomal recessive mitochondrial leukoencephalopathy caused by biallelic pathogenic variants in the IBA57 gene. The gene protein product, IBA57, has an unknown role in iron-sulfur (Fe-S) cluster biogenesis but is required for the maturation of mitochondrial [4Fe-4S] proteins. To better understand the role of IBA57 in MMDS3, we have investigated the impact of the pathogenic p.Gly104Cys (c.310G > T) variant on the structural and functional properties of IBA57. The Gly104Cys variant has been associated with a severe MMDS3 phenotype in both compound heterozygous and homozygous states, and defects in the activity of mitochondrial respiratory complexes and lipoic acid-dependent enzymes have been demonstrated in the affected patients. Size exclusion chromatography, also coupled to multiple angle light scattering, NMR, circular dichroism, and fluorescence spectroscopy characterization has shown that the Gly104Cys variant does not impair the conversion of the homo-dimeric [2Fe-2S]-ISCA22 complex into the hetero-dimeric IBA57-[2Fe-2S]-ISCA2 but significantly affects the stability of IBA57, in both its isolated form and in complex with ISCA2, thus providing a rationale for the severe MMDS3 phenotype associated with this variant.
Insights
The p.Gly104Cys variant in the IBA57 gene causes severe Multiple Mitochondrial Dysfunctions Syndrome type 3 (MMDS3) by destabilizing the IBA57 protein and its complexes, impacting mitochondrial function.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Multiple Mitochondrial Dysfunctions Syndrome type 3 (MMDS3) is a rare leukoencephalopathy.
- It results from pathogenic variants in the IBA57 gene, crucial for mitochondrial iron-sulfur protein maturation.
Purpose of the Study:
- Investigate the structural and functional impact of the p.Gly104Cys variant in IBA57.
- Understand the molecular basis of severe MMDS3 phenotypes associated with this variant.
Main Methods:
- Utilized size exclusion chromatography, multi-angle light scattering, NMR, circular dichroism, and fluorescence spectroscopy.
- Characterized the isolated and complexed forms of the Gly104Cys variant of IBA57 protein.
Main Results:
- The Gly104Cys variant did not prevent the formation of the IBA57-ISCA2 complex.
- This variant significantly reduced the stability of IBA57, both alone and when bound to ISCA2.
Conclusions:
- The instability of the IBA57 protein caused by the Gly104Cys variant provides a molecular explanation for severe MMDS3.
- This finding highlights the importance of IBA57 stability in mitochondrial health and disease.
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