Systematic surveys of iron homeostasis mechanisms reveal ferritin superfamily and nucleotide surveillance regulation to be modified by PINK1 absence

  • 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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Author:Jana KeyGND, Nesli Ece ŞenGND, Aleksandar ArsovićORCiD, Stella Krämer, Robert Hülse, Natasha Nadeem Khan, David MeierhoferORCiDGND, Suzana Gispert, Gabriele Koepf, Georg AuburgerORCiDGND
Parent Title (English):Cells
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/10/02
Date of first Publication:2020/10/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/11/16
Tag:CPT1A; Cyp46a1; Hmox1; Ireb2; MMP14; PYGL; Pgrmc1; Slc11a2; Slc25a37; Tfrc; iron overload versus deprivation; neurodegeneration; nucleotide metabolism; synuclein
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0