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  Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Key, J., Sen, N. E., Arsović, A., Krämer, S., Hülse, R., Khan, N. N., et al. (2020). Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence. Cells, 9(10): 2229. doi:10.3390/cells9102229.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-2256-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-225A-E
Genre: Journal Article

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 Creators:
Key, Jana, Author
Sen, Nesli Ece, Author
Arsović , Aleksandar, Author
Krämer, Stella, Author
Hülse, Robert, Author
Khan, Natasha Nadeem, Author
Meierhofer, David1, Author              
Gispert, Suzana, Author
Koepf, Gabriele, Author
Auburger, Georg, Author
Affiliations:
1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: synuclein; CPT1A; MMP14; PYGL; Tfrc; Ireb2; Pgrmc1; Hmox1; Cyp46a1; Slc11a2; Slc25a37; iron overload versus deprivation; nucleotide metabolism; neurodegeneration
 Abstract: Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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Language(s): eng - English
 Dates: 2020-09-292020-10-02
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.3390/cells9102229
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Title: Cells
Source Genre: Journal
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Publ. Info: Basel, Switzerland : MDPI
Pages: - Volume / Issue: 9 (10) Sequence Number: 2229 Start / End Page: - Identifier: CoNE: https://pure.mpg.de/cone/journals/resource/2073-4409