Mitochondrial iron-sulfur cluster dysfunction in neurodegenerative disease

Abstract

Growing evidence supports a role for mitochondrial iron metabolism in the pathophysiology of neurodegenerative disorders such as Friedreich ataxia (FRDA) and Parkinson disease (PD) as well as in the motor and cognitive decline associated with the aging process. Ironsulfur enzyme deficits and regional iron accumulation have been observed in each of these conditions. In spite of significant etiological, clinical and pathological differences that exist between FRDA and PD, it is possible that defects in mitochondrial iron-sulfur clusters (ISCs) biogenesis represent a common underlying mechanism leading to abnormal intracellular iron distribution with mitochondrial iron accumulation, oxidative phosphorylation deficits and oxidative stress in susceptible cells and specific regions of the nervous system. Moreover, a similar mechanism may contribute to the age-dependent iron accumulation that occurs in certain brain regions such as the globus pallidus and the substantia nigra. Targeting chelatable iron and reactive oxygen species appear as possible therapeutic options for FRDA and PD, and possibly other age-related neurodegenerative conditions. However, new technology to interrogate ISC synthesis in humans is needed to (i) assess how defects in this pathway contribute to the natural history of neurodegenerative disorders and (ii) develop treatments to correct those defects early in the disease process, before they cause irreversible neuronal cell damage.

Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery

“…Based on the amino acid sequences of Yfh1 and Isu1, the molecular weight and amino acid specificity of BS 3 , and the cleavage specificity of GluC, the software calculated all theoretical possible combinations of cross-linked peptides and compared them with the precursor peptide masses in the MS file (52). Each identified cross-linked peptide was then assigned a score based on a comparison between the theoretical fragmentation and the actual MS/MS spectrum of the crosslinked peptide (52).…”

“…To assess the suitability of using chemical cross-linking to probe the complex structure, fractions comprising the ϳ330-kDa peak (fractions 52-56) were pooled and incubated with a non-hydrolysable cross-linker, BS 3 , and then re-purified by size-exclusion chromatography (Fig. 1, A and C).…”

“…A complete loss of mitochondrial Fe-S cluster synthesis is therefore lethal, while partial defects typically result in mitochondrial dysfunction, multiple Fe-S enzyme deficits throughout the cell, and global iron imbalance (1). In humans, inherited defects in mitochondrial Fe-S cluster synthesis have been linked to the neurodegenerative disease Friedreich ataxia and to various tissue-specific conditions, although the role of this process in human disease is most likely underestimated (3).…”

The Structure of the Complex between Yeast Frataxin and Ferrochelatase

“…Low levels of frataxin in humans are responsible for the progressive neurodegenerative disease Friedreich's ataxia, caused by trinucleotide repeat expansions in the first intron of the frataxin gene and the consequent gene silencing. Frataxin deficiency results in aberrations in cellular iron homeostasis, progressive accumulation of iron in mitochondria, high levels of oxidative stress, and deficiency in heme and ISC biosynthesis (4,(7)(8)(9).…”

Mitochondrial Genes and Neurodegenerative Disease

“…Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by pathological GAA trinucleotide repeat expansions in the fi rst intron of the FXN gene [ 65 ]. The encoded protein, frataxin, is a mitochondrial matrix, 21 kDa polypeptide involved in the formation of iron-sulphur clusters, which are critical components of the mitochondrial respiratory chain complexes and of many redox enzymes not only in mitochondria, but also in the cytoplasm and nucleus.…”