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. Iron-sulfur 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.

Keywords: Friedreich ataxia; Parkinson disease; aging; anti-oxidants; iron-chelators; iron–sulfur clusters; mitochondria; oxidative damage.

FIGURE 1

Flow-chart representation of the steps and factors involved in the natural history of neurodegenerative disorders. See text for details.

FIGURE 2

Graphic representation of the three main modalities in the natural history of neurodegenerative disease. The rate of neurodegenerative disease progression is plotted as a function of age with an arbitrary threshold for appearance of clinical signs and symptoms. The plots show typical rates of progression for old age-related, late-onset and early-onset neurodegenerative disorders. The portion of each plot below the threshold represents the pre-symptomatic period during which the degenerative process is already active. FRDA, Friedreich ataxia; PD, Parkinson disease.

FIGURE 3

Molecular components involved in the initial step of mitochondrial ISC synthesis and their biological roles. When mitochondrial ISC synthesis functions normally, vital enzyme activities are maintained throughout the cell, iron-catalyzed oxidative damage is limited, and there is a balance between iron uptake and iron utilization. See text for additional details. NFS1, cysteine desulfurase; ISD11, adaptor protein required for NFS1 stability; ISCU, scaffold protein; I, II, III, respiratory chain complexes I, II, and III; Aco, mitochondrial aconitase; mtDNA, mitochondrial DNA; nDNA, nuclear DNA.

FIGURE 4

Proposed model for a role of ISC synthesis defects in PD progression. See text for details. Tf, transferrin; TfR2, transferrin receptor; other abbreviations are as in the legend for Figure 3.

FIGURE 5

A spectrum of clinical phenotypes may be linked to ISC synthesis defects. ISC synthesis defects of decreasing severity lead to a variety of clinical phenotypes ranging from embryonic lethality to increased predisposition to age-related disorders.