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.
Highlights
Intracellular iron metabolism in mammalian cells is crucial for their proper functions
The initial quality evaluation of stressed WT mouse embryonic fibroblast (MEF) cultures showed that iron overload mediated by ferric ammonium citrate (FAC) exposure triggered relatively few abundance changes, in comparison to iron shortage mediated by 2,20 -Bipyridine (22BP)
FAC, and newly identified a converse regulation for the iron-binding purine degradation subunits after 22BP versus FAC, and newly identified a converse regulation for the iron-binding purine degradation enzyme XDH, the mitochondrial lipid transporter CPT1A, the collagen degrading factor MMP14, and the glycogen mobilizing enzyme PYGL
Summary
Intracellular iron metabolism in mammalian cells is crucial for their proper functions. Cells 2020, 9, 2229 detoxification and distributed within cells, for example to mitochondria, where iron is utilized for iron-sulfur-cluster (ISC) production and heme generation [2,3,4]. The correct function of dozens of proteins in mitochondria, cytosol, and nucleus depends on the insertion of ISC [5,6], so the regulation of iron homeostasis is crucial. Heme is needed as a cofactor of cytochrome proteins within mitochondria, and of cytosolic cytochrome P450 proteins, globins, iron-regulatory proteins, peroxidases, catalase, and specific ion-channels [10]
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