論文

国際誌
2020年12月17日

Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.

Molecular cell
  • Felix A Dingler
  • ,
  • Meng Wang
  • ,
  • Anfeng Mu
  • ,
  • Christopher L Millington
  • ,
  • Nina Oberbeck
  • ,
  • Sam Watcham
  • ,
  • Lucas B Pontel
  • ,
  • Ashley N Kamimae-Lanning
  • ,
  • Frederic Langevin
  • ,
  • Camille Nadler
  • ,
  • Rebecca L Cordell
  • ,
  • Paul S Monks
  • ,
  • Rui Yu
  • ,
  • Nicola K Wilson
  • ,
  • Asuka Hira
  • ,
  • Kenichi Yoshida
  • ,
  • Minako Mori
  • ,
  • Yusuke Okamoto
  • ,
  • Yusuke Okuno
  • ,
  • Hideki Muramatsu
  • ,
  • Yuichi Shiraishi
  • ,
  • Masayuki Kobayashi
  • ,
  • Toshinori Moriguchi
  • ,
  • Tomoo Osumi
  • ,
  • Motohiro Kato
  • ,
  • Satoru Miyano
  • ,
  • Etsuro Ito
  • ,
  • Seiji Kojima
  • ,
  • Hiromasa Yabe
  • ,
  • Miharu Yabe
  • ,
  • Keitaro Matsuo
  • ,
  • Seishi Ogawa
  • ,
  • Berthold Göttgens
  • ,
  • Michael R G Hodskinson
  • ,
  • Minoru Takata
  • ,
  • Ketan J Patel

80
6
開始ページ
996
終了ページ
1012
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.molcel.2020.10.012

Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.

リンク情報
DOI
https://doi.org/10.1016/j.molcel.2020.10.012
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33147438
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758861

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