PMID- 36351893
OWN - NLM
STAT- MEDLINE
DCOM- 20221117
LR  - 20230121
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 11
DP  - 2022 Nov 9
TI  - Oxidative degradation of dihydrofolate reductase increases CD38-mediated 
      ferroptosis susceptibility.
PG  - 944
LID - 10.1038/s41419-022-05383-7 [doi]
LID - 944
AB  - High expression of CD38 in tissues is a characteristic of aging, resulting in a 
      decline in nicotinamide adenine dinucleotide (NAD) and increasing cellular 
      reactive oxygen species (ROS). However, whether CD38 increases susceptibility to 
      ferroptosis remains largely unexplored. Our previous study showed that CD38 
      overexpression decreased dihydrofolate reductase (DHFR). In the present study, we 
      confirmed that high expression of CD38 increased ROS levels and induced DHFR 
      degradation, which was prevented by nicotinamide mononucleotide (NMN) 
      replenishment. We further revealed that ROS-mediated sulfonation on Cys7 of DHFR 
      induced its degradation via the autophagy and non-canonical proteasome pathways. 
      Mutation of Cys7 to alanine abolished ROS-induced DHFR degradation. Moreover, 
      oxidative degradation of DHFR was responsible for the increased ferroptosis 
      susceptibility of cells in which CD38 was highly expressed. We also found that 
      CD38 expression was higher in bone-marrow-derived macrophages (BMDMs) from aged 
      mice than those from young mice, while the DHFR level was lower. Consequently, we 
      demonstrated that BMDMs from aged mice were more susceptible to ferroptosis that 
      can be reverted by NMN replenishment, suggesting that CD38 high expression 
      rendered cells more susceptible to ferroptosis. Taken together, these results 
      indicated that CD38-mediated NAD(+) decline promoted DHFR oxidative degradation, 
      thus resulting in increased cellular susceptibility to ferroptosis and suggesting 
      that NMN replenishment may protect macrophages from ferroptosis in aged mice.
CI  - (c) 2022. The Author(s).
FAU - Ma, Yingying
AU  - Ma Y
AD  - MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic 
      Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
FAU - Yi, Meiqi
AU  - Yi M
AD  - BeiGene (Beijing) Co., Ltd., 100084, Beijing, China.
FAU - Wang, Weixuan
AU  - Wang W
AUID- ORCID: 0000-0002-2613-589X
AD  - Institute of Chinese Medicine, Guangdong Pharmaceutical University, 510006, 
      Guangzhou, China.
FAU - Liu, Xiaohui
AU  - Liu X
AD  - MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic 
      Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
FAU - Wang, Qingtao
AU  - Wang Q
AD  - Beijing Chao-yang Hospital, Capital Medical University, 100043, Beijing, China.
FAU - Liu, Chongdong
AU  - Liu C
AD  - Beijing Chao-yang Hospital, Capital Medical University, 100043, Beijing, China.
FAU - Chen, Yuling
AU  - Chen Y
AUID- ORCID: 0000-0002-8399-2070
AD  - MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic 
      Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China. 
      chenyuling2016@mail.tsinghua.edu.cn.
FAU - Deng, Haiteng
AU  - Deng H
AUID- ORCID: 0000-0001-9496-1280
AD  - MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic 
      Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China. 
      dht@mail.tsinghua.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221109
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0U46U6E8UK (NAD)
RN  - 1094-61-7 (Nicotinamide Mononucleotide)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
RN  - EC 3.2.2.5 (Cd38 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Ferroptosis
MH  - *NAD/metabolism
MH  - Nicotinamide Mononucleotide/pharmacology
MH  - Oxidative Stress
MH  - Reactive Oxygen Species/metabolism
MH  - Tetrahydrofolate Dehydrogenase/genetics
PMC - PMC9646779
COIS- The authors declare no competing interests.
EDAT- 2022/11/10 06:00
MHDA- 2022/11/15 06:00
PMCR- 2022/11/09
CRDT- 2022/11/09 23:13
PHST- 2022/06/04 00:00 [received]
PHST- 2022/10/26 00:00 [accepted]
PHST- 2022/10/21 00:00 [revised]
PHST- 2022/11/09 23:13 [entrez]
PHST- 2022/11/10 06:00 [pubmed]
PHST- 2022/11/15 06:00 [medline]
PHST- 2022/11/09 00:00 [pmc-release]
AID - 10.1038/s41419-022-05383-7 [pii]
AID - 5383 [pii]
AID - 10.1038/s41419-022-05383-7 [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Nov 9;13(11):944. doi: 10.1038/s41419-022-05383-7.