# A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease

## TL;DR

A new mutation in the FDX2 gene is linked to a rare mitochondrial disease, MEOAL, causing muscle weakness and other symptoms.

## Contribution

A novel homozygous FDX2 mutation is identified and studied for its role in MEOAL pathogenesis.

## Key findings

- The FDX2 mutation causes altered splicing and a modified protein structure.
- Patient cells show reduced FDX2 levels and impaired mitochondrial function.
- Mutant FDX2 likely retains function but leads to FeS protein defects and mitochondrial iron accumulation.

## Abstract

Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is a rare autosomal recessive neuromuscular disorder characterized by childhood onset of progressive muscle weakness and exercise intolerance. It is caused by mutations in the FDX2 gene, encoding the mitochondrial protein ferredoxin 2 (FDX2), a central component of the cellular FeS protein biogenesis. To date there are gaps in our understanding of how FDX2 mutations impact mitochondrial pathophysiology in MEOAL patients. In this work we report a multidisciplinary study of a pediatric patient with a diagnosis of neuromuscular disorder, with multiorgan involvement, associated with a novel homozygous mutation in FDX2, i.e., c.200+4 A > G. We found that: (i) the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids; (ii) patient’s cells have low levels of FDX2; (iii) the mutant FDX2 likely retains its functional integrity, as can be inferred by the absence of significant structural or backbone dynamic differences relative to the wild type protein; (iv) cultured patient’s cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation; (v) the levels of the mitochondrial SOD2 are significantly diminished in patient’s cells and may contribute to weak ROS production. Collectively, the results show that the FDX2 mutation leads to a severe decrease of FDX2 protein, resulting in a primary mild cellular FeS protein assembly defect and in the secondary consequences mentioned above, that together may explain the pathogenesis of this MEOAL case.