Preprint Article Version 1 This version is not peer-reviewed

Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin

Version 1 : Received: 21 October 2019 / Approved: 22 October 2019 / Online: 22 October 2019 (05:01:43 CEST)

How to cite: Key, J.; Sen, N.E.; Arsovic, A.; Krämer, S.; Hülse, R.; Gispert-Sanchez, S.; Auburger, G. Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin. Preprints 2019, 2019100252 (doi: 10.20944/preprints201910.0252.v1). Key, J.; Sen, N.E.; Arsovic, A.; Krämer, S.; Hülse, R.; Gispert-Sanchez, S.; Auburger, G. Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin. Preprints 2019, 2019100252 (doi: 10.20944/preprints201910.0252.v1).

Abstract

Lifespan extension was recently achieved in Caenorhabditis elegans nematodes by mitochondrial stress and mitophagy, triggered via iron depletion. Conversely in man, deficient mitophagy due to Pink1/Parkin mutations triggers iron accumulation in patient brain and limits survival. We now aimed to identify murine fibroblast factors, which adapt their mRNA expression to acute iron manipulation, relate to mitochondrial dysfunction and may influence survival. After iron depletion, expression of the plasma membrane receptor Tfrc with its activator Ireb2, the mitochondrial membrane transporter Abcb10, the heme-release factor Pgrmc1, the heme-degradation enzyme Hmox1, the heme-binding cholesterol metabolizer Cyp46a1, as well as the mitophagy regulators Pink1 and Parkin showed a negative correlation to iron levels. After iron overload, these factors did not change expression. Conversely, a positive correlation of mRNA levels with both conditions of iron availability was observed for the endosomal factors Slc11a2 and Steap2, as well as for the iron-sulfur-cluster (ISC)-containing factors Ppat, Bdh2 and Nthl1. Positive correlation only after iron depletion was observed for the iron export factor Slc40a1, mitochondrial iron transporters Slc25a28, Abcb7 and Abcb8, mitochondrial ISC-containing factors Glrx5, Nfu1, Bola1 and Abce1, cytosolic Aco1 and Tyw5, as well as nuclear Dna2, Elp3, Pold1 and Prim2. The latter are regulators of nucleotide synthesis and DNA quality control, which have known importance for growth and lifespan. The only Pink1-/- triggered transcript modulation was the reduced expression of the ISC-containing ribosomal factor Abce1. These mammalian findings support previous fly data that Pink1 influences co-translational quality control via Abce1, as well as mitophagy. Our findings provide the first systematic survey how iron dosage triggers homeostatic transcriptional regulations and elucidate how iron deprivation results in mitophagy.

Subject Areas

ferric ammonium citrate; deferoxamine; 2,2′-bipyridine; iron homeostasis; ISC; mitochondrial clearance; longevity; starvation; Parkinson’s disease

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