Ulk1-mediated Atg5-independent macroautophagy mediates elimination of mitochondria from embryonic reticulocytes

  • Nature Communications 5, Article number: 4004 (2014)
  • doi:10.1038/ncomms5004
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Macroautophagy is a highly conserved intracellular process responsible for the degradation of subcellular constituents. Macroautophagy was recently suggested to be involved in the removal of mitochondria from reticulocytes during the final stage of erythrocyte differentiation. Although Atg5 and Atg7 are indispensable for macroautophagy, their role in mitochondrial clearance remains controversial. We recently discovered that mammalian cells use conventional Atg5/Atg7-dependent macroautophagy as well as an alternative Unc-51-like kinase 1 (Ulk1)-dependent Atg5/Atg7-independent macroautophagy process. We hypothesized that the latter may be involved in mitochondrial clearance from reticulocytes during erythrocyte differentiation. Here we report that fetal definitive reticulocytes from Ulk1-deficient and Ulk1/Atg5 double-deficient mice retain their mitochondria, whereas the mitochondria are engulfed and digested within autophagic structures in wild-type and Atg5-deficient mice. Mitochondrial retention by Ulk1-deficient reticulocytes is far less marked in primitive and adult definitive reticulocytes. These data indicate that Ulk1-dependent Atg5-independent macroautophagy is the dominant process of mitochondrial clearance from fetal definitive reticulocytes.

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We are grateful to Dr N. Mizushima (University of Tokyo) for kindly providing Atg5−/− mice. We are also grateful to Drs. M. Komatsu and K. Tanaka (Rinshoken) for kindly providing Atg7-flox mice. This work was supported in part by the Grant-in-Aid for Scientific Research on Innovative Areas, Grant-in-Aid for Scientific Research (S), Grant-in-Aid for challenging Exploratory Research, Grant-in-Aid for Young Scientists (A) from the MEXT of Japan and a grant for the Scientific Technique Research Promotion Programme for Agriculture, Forestry, Fisheries and Food Industry. This study was also supported by grants from the following sources: The Secom Science and Technology Foundation, The Takeda Science Foundation, The Uehara Memorial Foundation, The Sumitomo Foundation and The SENSHIN Medical Research Foundation.

Author information


  1. Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

    • Shinya Honda
    • , Satoko Arakawa
    • , Yuya Nishida
    • , Hirofumi Yamaguchi
    •  & Shigeomi Shimizu
  2. Department of Pediatrics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan

    • Eiichi Ishii


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S.H. designed the research and performed biological analyses, Y.N. and H.Y. performed biological analyses, S.A. performed EM analyses, E.I. advised data interpretation, and S.S. designed the research and wrote the manuscript. All authors edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shigeomi Shimizu.

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