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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 <i>Nthl1-Ppat-Bdh2</i>, but also mitochondrial <i>Glrx5</i>-<i>Nfu1</i>-<i>Bola1</i>, cytosolic <i>Aco1-Abce1-Tyw5</i>, and nuclear <i>Dna2</i>-<i>Elp3</i>-<i>Pold1</i>-<i>Prim2</i>. Incidentally, upregulated <i>Pink1</i>-<i>Prkn</i> levels explained mitophagy induction, the downregulated expression of <i>Slc25a28</i> 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 <i>Abce1</i> 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.