TY  - JOUR
A1  - Key, Jana
A1  - Şen, Nesli Ece
A1  - Arsović, Aleksandar
A1  - Krämer, Stella
A1  - Hülse, Robert
A1  - Khan, Natasha Nadeem
A1  - Meierhofer, David
A1  - Gispert, Suzana
A1  - Koepf, Gabriele
A1  - Auburger, Georg
T1  - Systematic surveys of iron homeostasis mechanisms reveal ferritin superfamily and nucleotide surveillance regulation to be modified by PINK1 absence
T2  - Cells
N2  - 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.
KW  - synuclein
KW  - CPT1A
KW  - MMP14
KW  - PYGL
KW  - Tfrc
KW  - Ireb2
KW  - Pgrmc1
KW  - Hmox1
KW  - Cyp46a1
KW  - Slc11a2
KW  - Slc25a37
KW  - iron overload versus deprivation
KW  - nucleotide metabolism
KW  - neurodegeneration
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56911
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-569114
SN  - 2073-4409
VL  - 9
IS  - 2229
PB  - MDPI
CY  - Basel
ER  -