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.
Highlights
Reviewed by: Stanislav Yanev, Institute of Neurobiology – Bulgarian Academy of Sciences, Bulgaria Zvi Ioav Cabantchik, Hebrew University of Jerusalem, Israel Francesc Palau, Centro de Investigación Príncipe Felipe, Spain
In spite of significant etiological, clinical and pathological differences that exist between Friedreich ataxia (FRDA) and Parkinson disease (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
THE NATURAL HISTORY OF NEURODEGENERATIVE DISEASE neurodegenerative disorders can present at different ages and with a broad variety of symptoms, their natural histories can be recapitulated by a few common steps (Figure 1): Normally developed and overall healthy neuronal cells are exposed to an insult that initiates the neurodegenerative process; this leads to progressive neuronal cell dysfunction and death, which leads to clinical signs and symptoms of neurological impairment
Summary
Peripheral nervous systems (Zecca et al, 1996; Bartzokis et al, 2004; Boddaert et al, 2007; Oakley et al, 2007; Koeppen, 2011); (ii) cellular iron re-distribution within affected cell types that may result in mitochondrial iron accumulation and iron-catalyzed Fenton chemistry (Zecca et al, 2004a; Whitnall et al, 2008; Mastroberardino et al, 2009); and (iii) the presence of iron–sulfur enzyme deficits (Rotig et al, 1997; Longo et al, 1999; Betarbet et al, 2000) [reviewed in (Xu et al, 2010; Gille and Reichmann, 2011; Vaubel and Isaya, 2013; Table 1)] This evidence supports the view that a common underlying mechanism involving iron metabolism–namely, defects in the biogenesis of mitochondrial iron–sulfur clusters (ISCs) and related enzymes–contributes to FRDA, PD and the aging process, in spite of these three conditions.
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