Details

Autor(en) / Beteiligte

• Seguin, Alexandra
• Jia, Xuan
• Earl, Aubree M.
• Li, Liangtao
• Wallace, Jared
• Qiu, Andong
• Bradley, Thomas
• Shrestha, Rishna
• Troadec, Marie-Bérengère
• Hockin, Matt
• Titen, Simon
• Warner, Dave E.
• Dowdle, P. Tom
• Wohlfahrt, Martin E.
• Hillas, Elaine
• Firpo, Matthew A.
• Phillips, John D.
• Kaplan, Jerry
• Paw, Barry H.
• Barasch, Jonathan
• Ward, Diane M.

Titel

The mitochondrial metal transporters mitoferrin1 and mitoferrin2 are required for liver regeneration and cell proliferation in mice

Ist Teil von

• The Journal of biological chemistry, 2020-08, Vol.295 (32), p.11002-11020

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Mitochondrial iron import is essential for iron–sulfur cluster formation and heme biosynthesis. Two nuclear-encoded vertebrate mitochondrial high-affinity iron importers, mitoferrin1 (Mfrn1) and Mfrn2, have been identified in mammals. In mice, the gene encoding Mfrn1, solute carrier family 25 member 37 (Slc25a37), is highly expressed in sites of erythropoiesis, and whole-body Slc25a37 deletion leads to lethality. Here, we report that mice with a deletion of Slc25a28 (encoding Mfrn2) are born at expected Mendelian ratios, but show decreased male fertility due to reduced sperm numbers and sperm motility. Mfrn2−/− mice placed on a low-iron diet exhibited reduced mitochondrial manganese, cobalt, and zinc levels, but not reduced iron. Hepatocyte-specific loss of Slc25a37 (encoding Mfrn1) in Mfrn2−/− mice did not affect animal viability, but resulted in a 40% reduction in mitochondrial iron and reduced levels of oxidative phosphorylation proteins. Placing animals on a low-iron diet exaggerated the reduction in mitochondrial iron observed in liver-specific Mfrn1/2-knockout animals. Mfrn1−/−/Mfrn2−/− bone marrow–derived macrophages or skin fibroblasts in vitro were unable to proliferate, and overexpression of Mfrn1-GFP or Mfrn2-GFP prevented this proliferation defect. Loss of both mitoferrins in hepatocytes dramatically reduced regeneration in the adult mouse liver, further supporting the notion that both mitoferrins transport iron and that their absence limits proliferative capacity of mammalian cells. We conclude that Mfrn1 and Mfrn2 contribute to mitochondrial iron homeostasis and are required for high-affinity iron import during active proliferation of mammalian cells.