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Review
. 2020 Oct 20;9(10):1020.
doi: 10.3390/antiox9101020.

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Isabel Hinarejos  1   2 , Candela Machuca-Arellano  1   2   3 , Paula Sancho  1   2 , Carmen Espinós  1   2   4
Affiliations
Review

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Isabel Hinarejos et al. Antioxidants (Basel). .

Abstract

The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

Keywords: autophagy; brain iron accumulation; iron metabolism; lipid metabolism; membrane remodelling; mitochondrial dysfunction; neurodegenerative disorder; neuroinflammation; oxidative stress; rare disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pathway connecting lipid synthesis, lysosomes dysfunction and iron accumulation in NBIA syndromes. PANK2, COASY, FA2H and PLA2G6 defects lead to harmed phospholipid membrane synthesis and impaired myelination or myelin maintenance. Dysfunctional membranes may lead to lysosomal and mitochondrial damage causing ROS production and iron uptake upregulation. WDR45 and ATP13A2 are involved in autophagosome formation/degradation. The decrease of WDR45 protein expression causes the accumulation of aberrant autophagic structures. Lysosomal dysfunction due to ATP13A2 defect, which may originate from impaired phospholipid recycling, could ultimately cause degradation of substrates and damage of autophagosome clearance. Moreover, perturbation of lysosomes is important for iron homeostasis and may promote deposits of iron. Dysfunction of FTL prevents the recruitment of iron excess and malfunctioning of CP causes impairment of iron export from the cell, responsible for iron overload. The higher free iron-dependent oxidative damage requires that the cell increases the degradation of oxidized molecules, which can affect the cellular recycling systems, such as lysosomes, and finally, lead to cellular death. The role of DCAF17 remains unclear, although its dysfunction leads to a neurodegenerative disorders, and hence, in some way, DCAF17 may be related to mitochondrial dynamics.
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