Molecular Neurobiology

, Volume 53, Issue 8, pp 5542–5574 | Cite as

Iron and Neurodegeneration: Is Ferritinophagy the Link?

  • Giorgio Biasiotto
  • Diego Di Lorenzo
  • Silvana Archetti
  • Isabella Zanella


Mounting evidence indicates that the lysosome-autophagy pathway plays a critical role in iron release from ferritin, the main iron storage cellular protein, hence in the distribution of iron to the cells. The recent identification of nuclear receptor co-activator 4 as the receptor for ferritin delivery to selective autophagy sheds further light on the understanding of the mechanisms underlying this pathway. The emerging view is that iron release from ferritin through the lysosomes is a general mechanism in normal and tumour cells of different tissue origins, but it has not yet been investigated in brain cells. Defects in the lysosome-autophagy pathway are often involved in the pathogenesis of neurodegenerative disorders, and brain iron homeostasis disruption is a hallmark of many of these diseases. However, in most cases, it has not been established whether iron dysregulation is directly involved in the pathogenesis of the diseases or if it is a secondary effect derived from other pathogenic mechanisms. The recent evidence of the crucial involvement of autophagy in cellular iron handling offers new perspectives about the role of iron in neurodegeneration, suggesting that autophagy dysregulation could cause iron dyshomeostasis. In this review, we recapitulate our current knowledge on the routes through which iron is released from ferritin, focusing on the most recent advances. We summarise the current evidence concerning lysosome-autophagy pathway dysfunctions and those of iron metabolism and discuss their potential interconnections in several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases; amyotrophic lateral sclerosis; and frontotemporal lobar dementia.


Ferritinophagy Nuclear receptor co-activator 4 NCOA4 Iron Autophagy Lysosome Neurodegeneration 



Alzheimer’s disease


5′-Aminolevulinate synthase 2


Amyotrophic lateral sclerosis


Amyotrophic lateral sclerosis 2, juvenile


Amyloid plaques


Amyloid precursor protein (amyloid beta A4 precursor protein)


Autophagy related 5


Autophagy related 7


Autophagy related 9A


Autophagy related 11


ATPase type 13A2


Ataxin 2


Autophagic vacuole


Blood-brain barrier


Chromosome 9 open reading frame 72


Chromosome 19 open reading frame 12


Corticobasal degeneration


Charged multivesicular body protein 2B


Chaperone-mediated autophagy


Coenzyme-A synthase




Cathepsin C


d-Aminoacid oxidase


Duodenal cytochrome b (CYBRD1, cytochrome b reductase 1)


Divalent metal transporter 1 (SLC11A2, solute carrier family 11, proton-coupled divalent metal ion transporter, member 2)


Parkinson protein 7


Fatty acid 2 hydroxylase


F-box and leucine-rich repeat protein 5


Ferroportin 1 (SLC40A1, solute carrier family 40, iron-regulated transporter, member 1)




Ferritin heavy polypeptide 1


Ferritin light polypeptide


Frontotemporal lobar dementia


Mitochondrial ferritin


Friedreich’s ataxia


Fused in sarcoma (FUS RNA-binding protein)




GABA(A) receptor-associated protein


GABA(A) receptor-associated protein-like 1


GABA(A) receptor-associated protein-like 2


Glucocerebrosidase A1 (GBA, glucosidase beta, acid)




Heme carrier protein 1 (SLC46A1, solute carrier family 46, folate transporter, member 1)


Huntington’s disease




Hereditary ferritinopathy




Heme oxygenase 1 (HMOX1)


HtrA serine peptidase 2




Iron-responsive element


Iron regulatory protein 1 (ACO1, aconitase 1)


Iron regulatory protein 2 (IREB2, iron-responsive element-binding protein 2)


Lysosomal-associated membrane protein 1


Lysosomal-associated membrane protein 2


Microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A)


Labile iron pool


Leucine-rich repeat kinase 2


Lysosomal storage disease


Microtubule-associated protein tau


Mucolipin 1


Mouse embryonic fibroblast


Mitoferrin 1 (SLC25A37, solute carrier family 25 member 37)


Mitoferrin 2 (SLC25A28, solute carrier family 25 member 28)


Multiple system atrophy


Mechanistic target of rapamycin


Neurodegeneration with brain iron accumulation


Neighbour of BRCA1 gene 1


Nuclear receptor co-activator 4


Nuclear dot protein 52 (CALCOCO2, calcium binding and coiled-coil domain 2)


Neurofibrillary tangles


Non-transferrin bound iron




Pantothenate kinase 2




Poly rC-binding protein 1


Poly rC-binding protein 2


Parkinson’s disease


Profilin 1


Progranulin (GRN, granulin)


PTEN-induced putative kinase 1


Phospholipase A2 group VI


Presenilin 1


Presenilin enhancer γ-secretase subunit


Progressive supranuclear palsy


RAB29 member RAS oncogene family (PARK16, Parkinson disease 16)


RAB38 member RAS oncogene family


Reactive oxygen species


Stress granule


Sigma non-opioid intracellular receptor 1


Stable isotope labelling by amino acids in cell culture




α-Synuclein gene mutation


α-Synuclein gene multiplication


Superoxide dismutase 1


Superoxide dismutase 2, mitochondrial


Sequestosome 1


Sterol regulatory element-binding transcription factor 1


STEAP family member 3, metalloreductase


TAR DNA-binding protein (TARDBP)




Transcription factor EB


Transferrin receptor 1 (TFRC, transferrin receptor)


T cell immunoglobulin and mucin domain-2 (Timd2)


Transmembrane protein 106B


Transmembrane protease, serine 6




Ubiquilin 2


Ubiquitin carboxyl-terminal esterase L1


Ubiquitin proteasome system


Untranslated region


VAMP-associated protein B and C


Valosin-containing protein


Vacuolar protein sorting 35 (VPS35 retromer complex component)


WD repeat domain 45


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Biotechnology Laboratory, Department of DiagnosticsCivic Hospital of BresciaBresciaItaly

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