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

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.

Comprehensive Landscape of RRM2 with Immune Infiltration in Pan-Cancer

“…More importantly, RRM2 has been identified as a member of the ferric iron-binding ferritin-superfamily [ 19 ]. Shen et al have demonstrated that RRM2 engaged in the iron metabolism in hepatocellular carcinoma (HCC) [ 20 ].…”

The Effect of Cyanine Dye NK-4 on Photoreceptor Degeneration in a Rat Model of Early-Stage Retinitis Pigmentosa

“…Genes with expression change ≥ 1.4-fold and assembled data of four sets with a p value < 0.05 were selected for follow-up studies, and 15 genes ( Atf5, Trib3, Nexn, Mt1, Casp4, Hmox1, Bfsp2, Gcg, Ppic, Cdh3, Slc22a8, Ppfibp2, Slc7a11, Bdh2, C1qtnf5 ) were chosen for next analysis. Then, we checked the relevant literature to find the following five up-regulated genes as differentially expressed transcripts in the eyes treated with NK-4 that are related to anti-apoptosis: heme oxygenase 1 ( Hmox1) [ 28 ], metallothionein-1 (Mt1) [ 29 , 30 ], solute carrier family 7 member 11 (Slc7a11) [ 31 ], 3-hydroxybutyrate dehydrogenase 2 (Bdh2) [ 32 , 33 ], and activating transcription factor 5 (Atf5) [ 34 ] ( Table 1 ).…”

“…Bdh2 is expressed in all cell types in the retina to control iron homeostasis [ 32 ]. Bdh2 inhibition was found to result in cellular iron accumulation [ 33 ]. In the present study, we found that Bdh2 was up-regulated in NK-4-injected eyes, indicating that NK-4 may up-regulate the expression of Bdh2 to protect retina and RPE from damage by reducing excessive iron in the retina of RCS rats.…”

The Landscape of Iron metabolism-related Genes for Overall survival prediction in Patients with Hepatocellular carcinoma

“…[29]Animal experiments revealed that iron de ciency decreased the expression of RRM2 and reduced the protein abundance of RRM2. [30]And RRM2 may inhibit ferroptosis. [31] The expression level of CCNB1 was abnormally elevated in HCC and high expression is associated with better prognosis, as an oncogene, CCNB could inhibit the apoptosis of HCC cells and promote cell invasion.…”